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Review
Antimicrobial Nano-Agents: The Copper AgeClick to copy article linkArticle link copied!
- Maria Laura Ermini*Maria Laura Ermini*Email: [email protected]Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12-56126 Pisa, ItalyMore by Maria Laura Ermini
- Valerio Voliani*Valerio Voliani*Email: [email protected]Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12-56126 Pisa, ItalyMore by Valerio Voliani
ACS Nano
Cite this: ACS Nano 2021, 15, 4, 6008–6029
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Abstract
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The constant advent of major health threats such as antibacterial resistance or highly communicable viruses, together with a declining antimicrobial discovery, urgently requires the exploration of innovative therapeutic approaches. Nowadays, strategies based on metal nanoparticle technology have demonstrated interesting outcomes due to their intrinsic features. In this scenario, there is an emerging and growing interest in copper-based nanoparticles (CuNPs). Indeed, in their pure metallic form, as oxides, or in combination with sulfur, CuNPs have peculiar behaviors that result in effective antimicrobial activity associated with the stimulation of essential body functions. Here, we present a critical review on the state of the art regarding the in vitro and in vivo evaluations of the antimicrobial activity of CuNPs together with absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments. Considering the potentiality of CuNPs in antimicrobial treatments, within this Review we encounter the need to summarize the behaviors of CuNPs and provide the expected perspectives on their contributions to infectious and communicable disease management.
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License Summary*
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Attribution (BY): Credit must be given to the creator.
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
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Copyright © 2021 The Authors. Published by American Chemical Society
Introduction
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Infectious diseases are one of the major global health threats. Bacteria, viruses, and other microbes still cause millions of deaths every year, despite the wide development and commercialization of antivirals and antibiotics. (1,2)
Furthermore, an increasing occurrence of multi-drug-resistant (MDR) bacteria caused by antimicrobial drug consumption has been recognized in the past decades and still holds the attention of international health organizations. (3) In this regard, methicillin-resistant Staphylococcus aureus (MRSA) is one of the most dangerous resistant bacteria, being able to cause local skin infections, pneumonia, pericarditis, sepsis, and death. (3) The World Health Organization recommendations are to limit the exposure of bacteria to antibiotics in order to avoid the evolution and spread of resistance. (4,5) Indeed, increased awareness in the usage of existing drugs is one of the primary steps toward the reduction of the risks associated with MDR bacteria. (4,5) On the other hand, the development of approaches for the eradication of infections from persistent bacteria can help to avoid the issue of growing multi-drug resistance. (6,7) Among other microbes, viral infections are currently a huge concern and cause millions of deaths and hospitalizations every year. Examples include the avian influenza A (H5N1), the outbreak of severe acute respiratory syndrome (SARS), and the novel coronavirus (CoV) designated SARS-CoV. The high incidence of virus-related infections requires the discovery of effective and specific antiviral drugs and vaccines, which is very time demanding. (1)
In this scenario, the exploration of approaches for antimicrobial treatment and prevention is of special interest. In particular, the overarching goal of this field is to improve the strategies for the care of MDR-related infections by avoiding their diffusion as well as filling the lack of drugs that can target a broad spectrum of viruses. (4,8) In an era of declining antimicrobial discovery and rapidly emerging antibacterial resistance, treatment strategies based on metal nanoparticles technology are urgently required.
The combination of the antimicrobial activity of metals with nanotechnologies is increasingly being touted as the last-line defense toward communicable diseases. (9,10) Indeed, metal-based nanoparticles (NPs) have the peculiarity to be able to target multiple biomolecules and microbes compromising the development of resistant strains, as well as to be effective as antimicrobial agents through different mechanisms with respect to the classical treatments. (11)
The antimicrobial properties of bulk metals have been exploited for thousands of years. (12) For example, Cu and Ag have been used for water sanitization and food preservation since the time of the Persian kings, Ag foils have been historically used to prevent infection of surgical wounds, and compounds of copper have been extensively applied in agriculture as fungistatic on grapes and potatoes. (12) Compared to silver and gold, copper is cheaper and more easily accessible, while copper NPs (CuNPs) are biocompatible and can be synthesized by eco-friendly methods. (13) Copper-based nanoparticles have found several applications in many areas such as additives in skin product, metal coatings, inks, and plastic for food packaging. (14) In alloys, CuNPs have found applications in antimicrobial coatings in dentistry and virus disinfection. (15)
CuNPs demonstrate several crucial advantages with respect to other metallic NPs, among which are their cheaper and easier production. (16,17) CuNPs dissolve faster than other noble metals by releasing ions in the surroundings. (18) Concerning their antimicrobial activity, CuNPs generate oxidative stress, cause the disassembly of viruses or bacterial membranes, and can interfere with virus activity. (19) At the same time, copper ions increase the generation of compounds that are toxic for microbes. Copper is an essential element for human and other mammalian life, and it is involved in several pathways that are essential for living. (20−22) Thus, the copper ion release can enhance and support some of these pathways, such as the regeneration of tissues. (20−22) On the other hand, CuNPs may accumulate in the body (23,24) or release too many ions, causing long-term toxicity or contributing to the development of related diseases. (25)
In this Review, we have systematically analyzed the literature on the antimicrobial activity of copper-based NPs, critically reviewing the in vitro and in vivo antimicrobial studies for clinical purposes of pure metallic CuNPs, copper oxide nanoparticles (CuONPs), and copper sulfide nanoparticles (CuSNPs). While many works can be found about noble metal NPs, a more reduced group of works accounts for copper, and even less discusses comprehensively the potentiality of CuNPs. Nowadays, the peculiarities of CuNPs are still not completely recognized, possibly because CuNPs tend to dissolve as ions more easily with respect to other noble metals and because of the delicate equilibrium between their action and toxicity. This Review addresses this need in order to gather the behaviors of CuNPs together with their potentially relevant applications and the perspectives on their contributions to the next clinical applications in infectious and communicable diseases.
Antimicrobial Action of Copper Nanoparticles
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Even though copper is a fundamental element involved in several biological processes in living systems, it can exert a not-negligible toxic action on cells. (18,26)In vitro studies demonstrate that, at a certain range of concentrations, CuNPs can reduce the viability of cells, depending on the chemical composition, shape, and size of the nanomaterial. Karlsson et al. (26) showed that CuONPs (10–50 nm diameter) can cause oxidative stress and DNA damage to lung epithelial cells, reducing their viability to 50% after 18 h of exposure to 20 μg/mL (for more insights about CuNPs’ toxicity, refer to Biodistribution, Toxicity, and Persistence of CuNPs). In addition to oxidative stress, CuNPs can alter the metal ion homeostasis of cells. Each cell has a complex network of internal processes that regulates the concentration of copper inside a specific range. If cells are exposed to a higher dose than the amount that can be metabolized, the system can collapse. (20) Compared to the other metals commonly used in antimicrobial application, copper undergoes oxidation more easily and tends to dissolve in media as ions. (27,28) Copper ions and CuNPs can be considered redox-active species. (29) Indeed, they can subject the cell to oxidative stress through the generation of reactive oxygen species (ROS) which damage cellular components such as proteins, lipids, and nucleic acids. ROS are highly reactive species formed during the common cellular metabolism of oxygen, like ions or small molecules that contain peroxide, free radicals, or oxygen ions. They are normally involved in cell signaling, and cells are able to regulate their concentration thanks to several enzymes such as catalase or superoxide dismutase (SOD). When the ROS concentration is increased by the presence of external factors, like Cu species, the cell is subjected to oxidative stress that can bring to apoptosis. (29)
Several investigations have explored the different action that CuNPs and CuONPs exert on microbes. (30,31) In general, CuNPs are more prone to interact with the membrane of bacteria compromising its integrity. (26) Instead, CuONPs tend to penetrate the membrane of bacteria depending on the NP shape and releasing ions within the cell (the Trojan horse mechanism). (30,31) When NPs are immobilized on a surface of sol–gel silica, CuNPs exhibits a stronger antibacterial activity than CuO NPs. (3) The usual process that takes place for CuNPs is based on the redox equation which involves the energetically favorable oxidation of copper to Cu2+ (Cu(s) + O2 + 2H+ = Cu2+ + H2O2). Thus, the local production of hydrogen peroxide (and not the presence of ions) causes membrane damage. (32) This was confirmed by the work of Cronholm et al. that showed a minor impact on cell membrane when exposed to Cu ionic species. (33) Applerot et al. noticed that also CuONPs can produce ROS. Interestingly, E. coli is more affected by CuONPs than S. aureus, suggesting that the membrane differences between Gram-positive and Gram-negative bacteria can influence the resistance to ROS. (29) Furthermore, they evidenced a correlation between the amount of killed bacteria and the size of the NP. Briefly, they compared CuONPs of 30 and 2 nm diameter and highlighted that smaller NPs are more effective against bacteria. Indeed, 2 nm CuONPs disrupt and penetrate the bacterial membrane more efficiently than 30 nm CuONPs, as confirmed by transmission electron microscopy (TEM) images. Furthermore, smaller NPs are associated with an increased amount of superoxide anions, generating more intense oxidative stress. (29)
Laha et al. (34) demonstrated that the shape of the NP significantly influences the overall antibacterial activity by comparing the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of spherical CuONPs (33 nm) and nanosheets of CuO (257 × 42 nm). The first inhibit completely the growth of Gram-negative bacteria Proteus vulgaris and E. coli at concentrations of 0.16 and 0.20 mg/mL, while the second are more active on Gram-positive bacteria Bacillus subtilis and Micrococcus luteous (0.22 and 0.20 mg/mL, respectively). Both nanomaterials are able to damage the membrane of the bacteria (evaluated with electron microscopy) and DNA. Accordingly, with a higher dose of CUNPs (3200 μg/mL), Betancourt-Galindo et al. inhibited S. aureus and P. aeruginosain vitro above 99%. (35)
Zhou et al. (36) prepared 800 nm Cu2O@ZrP hybrid nanosheets with in situ reduction of Cu2+ on the surface of ZrP. They reported that this nanomaterial is highly effective (99% after 6 h) against two superbugs: methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). This strong effect is associated with the depolarization and damaging of the membrane of the bacteria. Moreover, ROS are produced and cause a toxic environment. These features can be also exploited in material coatings in order to avoid microbial proliferation. In this regard, CuONPs are particularly interesting against biofilm formation. (37) Zn-doped CuONPs have been deposited on catheters via ultrasound nanofabrication and employed against three pathogens commonly found in the urinary tract (E. coli, S. aureus, and Proteus mirabilis). (37) These substrates, tested in vivo on rats, have been able to delay or avoid urinary infection until day 7.
Several of the CuNPs evaluated for their antibacterial activity (Table 1) are biosynthesized. Natural compounds, directly extracted from plants or fermented, are often used as stabilizers for CuNPs synthesis. In this regard, plant-extracted compounds are generally ecofriendly and biocompatible, have low-toxicity, and may synergistically enhance the antimicrobial performances of CuNPs. (38) We would like to stress that the focus of this Review is to comprehensively discuss the antimicrobial activity of CuNPs. Thus, in the following we are just reporting a selection of the syntheses proposed to produce CuNPs. For a discussion with a focus on the production, we suggest the readers look elsewhere. (39−41)
Table 1. Summary of Size, Shape (Sphere-like if Not Specified), and Application of CuNPs
| authors/ref | NP size | target bacteria | application in vitro |
|---|---|---|---|
| Betancourt-Galindo et al., 2014 (35) | 4–12 nm | Pseudomonas aeruginosa (ATCC 13388) and Staphylococcus aureus (ATCC 6538) | in Petri dish |
| Rasool and Hemalatha, 2017 (44) | – | Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli, Salmonella typhimurium, and methicillin-resistant S. aureus | in Petri dish |
| Bocarando-Chacón et al., 2020 (45) | 10 nm | E. coli | in Petri dish |
| Laha et al., 2014 (34) | 33 nm spherical, | Bacillus subtilis (ATCC 6633), Micrococcus luteous (ATCC 9341), E. coli (ATCC 10,536), Proteus vulgaris (ATCC 13,387), and DH5a (kl2) | in Petri dish |
| 257 × 42 nm sheet | |||
| Chowdhury et al., 2013 (79) | 3 nm | S. aureus and E. coli | in natural fibers, oil palm empty fruit bunch fiber |
| Roy et al., 2016 (13) | 15 nm | S. aureus, Pseudomonas putida, and E. coli | using the leaf extract of Meliconia psittacorum |
| Marković et al., 2020 (83) | 30–40 nm | Gram-negative bacteria E. coli (ATCC 25922), E. coli (ATCC BAA 2469), and K. pneumoniae (ATCC BAA 2146); Gram-positive bacteria S. aureus (ATCC 25923) and S. aureus (ATCC 43300); and yeast Candida albicans (ATCC 24433) | NPs grown on bleached cotton woven fabric |
| Sathiyavimal et al., 2018 (82) | 50 nm | Gram-negative (E. coli and P. vulgaris) and Gram-positive (S. aureus) bacteria | synthesized using Sida acuta leaf extract, incorporated into cotton fabric |
| Amorim et al., 2019 (46) | 10 nm | S. aureus (ATCC 29213) | cashew gum |
| Valencia et al., 2020 (80) | 20 | Gram-negative (E. coli) and Gram-positive (Listeria innocua) bacteria | cellulose nanofibril |
| Shahidi et al., 2018 (81) | 40 and 100 nm | S. aureus (Gram-positive) | cotton fabric obtained with laser ablation |
| Delgado et al., 2011 (42) | 10–40 nm | E. coli | in a polypropylene matrix |
| Yaqub et al., 2020 (48) | 20 nm | P. aeruginosa and E. coli | with doxycycline |
| Villanueva et al., 2016 (73) | 63–160 nm | Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria | starch hydrogel |
| Cady et al., 2011 (75) | – | Acinetobacter baumannii | on cellulose |
| Vuković et al., 2015 (72) | – | E. coli, S. aureus, and C. albicans | hydrogel |
| Tang et al., 2018 (69) | 50 nm | E. coli | polyethylenimine-stabilized NPs, embedded in agar |
| El-Batal et al., 2018 (38) | 35 nm | K. pneumoniae, S. aureus, and C. albicans | in Petri dish |
| Sankaref et al., 2015 (52) | 577 nm | K. pneumoniae, Shigella dysenteriae, S. aureus, Salmonella typhimurium, and E. coli | copper oxide with Ficus religiosa leaf extract |
| Applerot et al., 2012 (29) | 2 and 30 nm | Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria | antibacterial mechanism of CuO NPs |
| Balcucho et al., 2020 (68) | 191 nm | methicillin-resistant S. aureus | polymer (polycaprolactone) |
| Jayaramudu et al., 2020 (70) | 8 nm | Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria | chitosan hydrogel |
| Gutierrez et al., 2019 (78) | 20–50 nm | E. coli and S. aureus | 3D-printed alginate hydrogel |
| Yin et al., 2014 (93) | 40 nm | Gram-positive oxacillin drug-resistant S. aureus and Gram-negative kanamycin drug-resistant E. coli | CuS NPs on the surface of NaYF4:Mn/Yb/Er@photosensitizer-doped SiO2 |
| Zhou et al., 2019 (36) | 800 nm | methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) | Cu2O@ZrP nanosheet |
| authors/ref | NP size | target microbes | application in vivo |
|---|---|---|---|
| Sankar et al., 2015 (52) | 577 nm | K. pneumoniae, Shigella dysenteriae, S. aureus, Salmonella typhimurium, and E. coli | wound healing on albino rats |
| Li et al., 2016 (67) | 40–50 nm | cell attachment and proliferation of human umbilical vein endothelial cells (HUVECs), angiogenesis-related gene expression, vascularization by ELISA | wound healing on albino rats |
| Zangeneh et al., 2019 (53) | – | Candida albicans, Candida glabrata, Candida krusei, Candida guilliermondii, P. aeruginosa, E. coli, B. subtilis, S. aureus, Salmonella typhimurium, and Streptococcus pneumonia | wound healing and antioxidant |
| Alizadeh et al., 2019 (51) | 20, 40, 80 nm | cell migration, proliferation of endothelial and fibroblast cells, and collagen deposition | different sizes and different concentrations |
| Zhao et al., 2020 (47) | 30 nm | cytotoxicity, and antifungal and antibacterial screening | wound healing evaluated by the number of fibrocytes and the concentrations of hydroxyproline, hexuronic acid, and hexosamine |
| Zhou et al., 2020 (90) | 35 nm | – | hydrogel + photothermal |
| Tahvilian et al., 2019 (62) | 50 nm | four fungal species, namely Candida albicans (PFCC No. 89-1000), Candida glabrata (PFCC No. 164-665), Candida krusei (PFCC No. 52951), and Candida guilliermondii, and four bacterial species, namely P. aeruginosa (ATCC No. 27853), E. coli 0157:H7 (ATCC No. 25922), B. subtilis (ATCC No. 6633), S. aureus (ATCC No. 25923), Salmonella typhimurium (ATCC No. 14028), and Streptococcus pneumonia (ATCC No. 49619) | Allium saralicum, on wound healing |
| Gopal et al., 2014 (54) | 50 nm | – | wound healing in vivo, chitosan |
| Xiao et al., 2018 (43) | 30 nm | drug-resistant Gram-positive S. aureus and Gram-negative E. coli | infected wound healing in vivo, catalytic activity with H2O2 |
| Wang et al., 2020 (11) | 5 nm (roughness) | MRSA | in MRSA-infected wounds with GO |
| Qiao et al., 2019 (91) | 6 nm | drug-resistant Gram-negative bacterial ESBL E. coli and MRSA | in MRSA-infected wounds, photothermal with quantum dots of CuS |
| Tao et al., 2019 (55) | 88 nm | Gram-negative (E. coli) and Gram-positive (S. aureus) | CuNPs + hydrogel net for photothermal in vivo infected wounds |
| Shalom et al., 2017 | 35–95 nm | E. coli, S. aureus, and Proteus mirabilis | catheter-associated urinary tract infections prevention |
For example, CuNPs synthesized in the presence of actinomycetes were more effective in vitro against several pathogenic bacteria (Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, Salmonella typhimurium, and MRSA) with respect to gentamicin. (44) CuNPs produced in the presence of extracts of Opuntia ficusindica and Geranium demonstrated an antimicrobial effect on E. coli at a lowest concentration of NPs of 250 μg/mL. (45) Similarly, in vitro inhibition of bacteria growth has been observed with CuNPs prepared in the presence of Heliconia psittacorum (13) or fermented fenugreek (Trigonella foenum) powder under the action of Pleurotus ostreatus or stabilized with cashew gum. (38,46) The last work compares the action of copper ions released by copper sulfate in alginate matrix and CuNPs with ciprofloaxacin in a “zone of inhibition” test. Interestingly, the copper ion sample does not create any growth inhibition against K. pneumoniae, S. aureus, and Candida albicans. On the contrary, CuNPs evidenced a strong antibacterial and antifungal activity. Zhao et al. (47) investigated the sensitivity of fungal and bacterial strains to CuNPs prepared with leaf extract of Allium eriophyllum, in comparison with the extract alone and copper sulfate alone. All tested microbes were sensitive to CuNPs and to the extract. Noticeably, in almost all cases the MIC for CuNPs was about 2 times lower than with the extract and 4 times lower than with copper sulfate. (47) Yaqub et al. used extracts of ginger (Zingiber officinale) and garlic (Allium sativum) for the synthesis of CuNPs and NPs conjugated with doxycycline, an antibiotic. The antimicrobial activity of the green-synthesized NPs conjugated with the drug showed more pronounced results against P. aeruginosa with respect to garlic and ginger NPs, although similar to those with the drug alone. (48)
Mechanism of Action of CuNPs on Wound Healing
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The correct healing of wounds is still a challenging clinical problem frequently causing morbidity and mortality. (49) Bacteria can easily infect the exposed tissues in the injury and consequently alter or inhibit the healing process. Sometimes the healing can stop, and the wound converts into a chronic disease with associated difficulties for its management. A plethora of nanomaterials have been developed and studied for improving the offer of medicaments for these injuries. Nano-objects, such as quantum dots, nanotubes, liposomes, and metal NPs, have been exploited for their flexible applicability, antimicrobial properties, and ability for controlled release of a cargo. (50) Some materials are able to combine these two latter aspects, contributing at the same time to the disinfection of the wound and to the stimulation of the process of healing. In this regard, CuNPs ranging from 6 nm to about 600 nm (Table 1) can trigger ROS production, killing bacteria in the wound as well as releasing copper ions that can spur the healing process. (47,51−55)
Wound-healing evolution can be summarized in a series of cascade effects that take place after the injury occurs. (50,56) First, the platelets of the blood stick to the exposed area of the injury in order to block the bleeding (homeostasis). They change shape for better clotting and send chemical signals to promote the process of activation of fibrin. This forms a mesh that fixes the platelets to each other. Platelets also release several pro-inflammatory factors (prostaglandins, thromboxane, prostacyclins, and histamine). Second, in the inflammation phase, the dead cells and bacteria are cleared out from white blood cells. Third, the cells migrate and divide, stimulated by the platelet-derived growth factor (PDGF). (20) This is the proliferation phase, when the wound contracts because of tissue reconstruction. Fibroblasts form an extracellular matrix of fibronectin and collagen and contract to stretch the wound edges. In addition, blood vessels are formed (angiogenesis) and epithelialization occurs. Fibroblasts and endothelial cells are recruited from transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) secreted by platelets from the first step. Finally, in the last phase of remodeling, collagen realigns and the useless cells undergo apoptosis. (47)
Figure 1
Figure 1. Scheme of the several reactions in which copper plays a role in wound healing. Reprinted with permission from ref (20). Copyright 2016 Elsevier.
Copper is involved in the homeostasis phase since the cells need to internalize copper ions for its employment in several pathways naturally essential for the correct metabolism of cells. Under physiological conditions, copper is involved in several oxidation–reduction cycles thanks to the relatively easy interconversion among the different oxidation states. (57) For instance, copper is the metal ion in cytochrome c oxidase involved in the biosynthesis of neurotransmitters in neuropeptide biosynthesis, or in the action of Zn-SOD against ROS. (57) On the cell membrane, the so-called high-affinity copper uptake protein 1 (Ctr1) is responsible for copper transport inside the cell. Ions are either reduced by plasma membrane reductase or moved by copper chaperone proteins. Mitochondria can receive copper ions in order to insert them in cytochrome c oxidase or to redirect them to post Golgi compartments or to cytosolic enzymes. The cell is equipped with a complex system for internal regulation of the amount of copper ion, so that, when the concentration is too high, copper is moved from adenosine triphosphatase 7A (ATP7A) from the Golgi network to the membrane for expulsion. (20)
In the wound-healing process, during the proliferation phase, PDGF-induced migration of vascular smooth muscle cells (VSMCs) is dependent on ATP7A activity, which is copper dependent. In the presence of a wound scratch, if ATP7A is depleted, VSMC migration is inhibited and the decrease of copper concentration is blocked, too. (58) In the same phase and in the following one, i.e., proliferation and remodeling, copper also acts in a complex with a peptide (GHK, glycyl-l-histidyl-l-lysine) to enhance the synthesis of collagen and to modulate the activity of metalloproteinases. (59) At the end of proliferation phase, the wounded skin becomes stronger thanks to aldehyde cross-links on collagen and elastin. This process is catalyzed by the enzyme lysyl oxidase, which is copper dependent: low concentration of copper leads to poor wound healing. (20)
Copper availability is also implicated in angiogenesis: the stimulation of vessel formation is imputed to the copper regulation of angiogenin and VEGF, the most effective mediator in the process of vessel formation. In particular, the concentration of copper ion can accelerate the wound healing and favors the creation of a tissue with better quality (high density of the cells’ hyperproliferative epidermis), as demonstrated by Sen et al. by treating wounds in mice with copper sulfate. (60) Nerve growth factor (NGF) contributes to angiogenesis, too, and its function is modulated by copper concentration. Copper can trigger NGF for neurite outgrowth or can inhibit NGF-mediated survival, avoiding the cell death induced by hydrogen peroxide from oxidative stress. (61)
As they are involved in so many fundamental processes, CuNPs can provide the copper needed for basic functionalities as well as supplement the system with a boost of metal, speeding up and promoting the quality of the overall process.
CuNPs as Antimicrobial and Wound-Healing Enhancers
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The wound-healing potential of CuNPs has been recently subjected to several investigations. The antimicrobial activity is synergic with the healing effect since the presence of infection can enhance and prolong inflammation and slow down the healing process. Zhao et al. (47) demonstrated that CuNPs prepared with A. eriophyllum leaf extract can remove bacteria and fungi in wounds while contributing to the healing of cutaneous injuries. Their NPs were able to increase the fibrocyte/fibroblast ratio at day 10 from administration compared with samples treated with copper ions or plant extract alone. Furthermore, they observed a regulation of the inflammation (lymphocytes, macrophages, and neutrophils). (47) Copper oxide NPs on wounds in male Wistar Albino rats prevented bleeding, microbial infection, and pus formation from the first days of treatment (NPs daily applied topically, for a period of 12 days, 20 mg/kg body weight), differently from control groups. (52) The wound size was more reduced in treated wounds compared with untreated animals, starting from the fourth day. Wounds treated with CuONPs showed higher degrees of re-epithelialization, higher amounts of collagen, and improved formation of capillaries.
Zangeneh et al. (53) demonstrated in vitro the antibacterial and antifungal properties of green-synthesized CuNPs from an aqueous extract of Falcaria vulgaris on a wide group of microbes with Agar well-diffusion and disk-diffusion methods (see Table 1). Akin to the paper described above, they confirmed that the wound-healing improvement resulted from the application of CuNPs on wounds in vivo. In particular, they observed an increase of fibrocytes, hexosamine, hexuronic acid, and hydroxyproline (major components of collagen). Furthermore, they noticed a regulation in the number of lymphocytes, macrophages, and neutrophils at day 10, meaning that the inflammation process is regulated and the healing is facilitated. (53) Tahvilian et al. (62) obtained comparable results with CuNPs prepared with Allium saralicum. The antibacterial and antifungal activities were compared with those of copper sulfate alone, the plant extract alone, and some common antibiotics and antifungal compounds. Almost all of the tested bacteria and fungi were affected by CuNPs@Allium, and their antibacterial and antifungal activities were more intense than those of standard antibiotics. The wound-healing effect was comparable with that reported in the paper from Zangeneh et al., suggesting that the antioxidant activity of CuNPs, measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, also contributes to moderate the inflammation and the pus production in the wounds.
Alizadeh et al. accounted for the influence of size and concentration on antimicrobial activity of CuNPs in the in vivo wound treatment. Several concentrations (1 μM, 10 μM, 100 μM, 1 mM, and 10 mM) and three NP diameters (20, 40, and 80 nm) were considered. The overall results did not indicate any defined trend. However, the smaller NPs were cytotoxic at all concentrations for endothelial cells, while they had no effect on viability of fibroblast and keratinocyte cells. The bigger NPs at the lower concentrations did not show accumulation in liver of the mice, which they enhanced endothelial cell migration and proliferation and stimulated tissue granulation and the growth of blood vessels. Similar results were obtained for 40 nm NPs and 1 mM concentration. (51)
CuNPs combined with other NPs were recently described as a highly effective antimicrobial wound healers both in vitro and in vivo. (11) In particular, CuS NPs were integrated with graphene oxide (GO) nanosheets to compose nanomaterials (CuS/GO nanocomposites (NCs)) that can both physically and chemically act on bacteria. In CuS/GO NCs, graphene nanosheets have a destructive effect on bacteria by two mechanisms: (i) the cell membrane of bacteria is damaged by severe insertion and cut, and (ii) lipid molecules are directly extracted, causing the collapse of the structure. (63) Briefly, this nanocomposite has a peculiar morphology that destroys bacteria through the “blade effect” (wrapping the cellular membranes) and damages the cell membrane by the needle-like structure. Furthermore, CuS/GO NCs have a peroxidase activity, generate ROS, favor the cell migration, and demonstrate low cytotoxicity and biocompatibility. CuS/GO NCs totally inhibit in vitro both E. coli and MRSA at a concentration of 100 μg/mL. Bacterial live/dead staining demonstrates the efficient killing property of CuS/GO NCs. After 24 h of contact, almost all bacteria were killed in vitro, in contrast to the use of GO alone, which killed only the half of the population in the same conditions. Both CuS/GO NCs and GO induce changes in bacteria morphology via cytoplasm shrinking and damage to the membrane. In addition, the adhesion of the bacteria is drastically reduced. This nanocomposite accelerates the wound healing in vivo on MRSA-infected wounds and eliminates the bacteria after 14 day of treatment.
In summary, these experimental works confirm the ability of CuNPs to assist and increase the wound-healing process and synergistically sanitize the surroundings with a combination of effects that depends on the size, the chemical nature, and the design of the nanomaterial.
CuNPs Embedded in a Matrix: Wound Dressing
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The risk that a wound can be infected is reduced if the wound site is covered with a material with specific antimicrobial properties. The suitable wound dressing should first create a layer on the exposed tissues in order to provide sterile protection against external pathogens and further traumas. It should be biocompatible so as to not affect the viability of the cells, and it should keep the conditions for better healing (i.e., keep the wound site moist to enhance the cell migration). Polymers, hydrogels, creams, tissues, and fibers are just some of the materials proposed in the literature as suitable candidates in wound healing. (56) Overall, infections can be prevented while promoting healing by incorporating an active agent inside the material. NPs can find a useful application in this scenario, (64,65) and CuNPs as antimicrobial agents and wound-healing promoters are increasingly incorporated in membranes, polymers, polysaccharides, hydrogels, fibers, and tissues, as discussed below. It is worth noting that such topical pharmaceuticals, like the copper-based ones, constitute one of the last resources for wound healing and are usually effectively incorporated with other therapeutics for enhancing the natural healing process and considering the overall clinical condition of the patient. (66)
Membrane
A very particular substrate for wound dressing was reported by Li et al. (67) They combined CuNPs-coated bioactive glass (Cu-BG) with natural eggshell membrane (ESM). The ESM is peeled off from eggs, dried, and subsequently decorated with Cu-containing glass ceramic disks via laser ablation. The purpose of the ESM is to improve hydrophilicity to the systems, while the decoration with copper enhances the hardness of the natural membrane. This material reduces the viability of E. coli of 90% both in vitro and in vivo and stimulates angiogenesis. VEGF, angiogenesis-related gene expression (VEGF, HIF-1a, VEGF receptor 2), and endothelial nitric oxide were improved in vitro when the dressing was tested on human umbilical vein endothelial cells (HUVECs). When applied directly on rat injuries, the substrate contributed to enhance the healing quality and time (i.e., improved angiogenesis and formation of uniform epidermis). Immunofluorescence staining of CD31, a transmembrane protein expressed early in vascular development, showed a higher density of vessels on the copper-containing substrate (5Cu-BG/ESM in Figure 2) with respect to control, ESM alone, and substrates without copper (0Cu-BG/ESM groups in Figure 2).
Figure 2
Figure 2. Left: SEM images showing the morphology of substrates with different amount of CuNPs at two magnifications: (a, b) outer eggshell membrane (ESM), (c, d) 0Cu-BG/ESM, (e, f) 2Cu-BG/ESM, and (g, h) 5Cu-BG/ESM. Right: Detection of increased vessel by immunofluorescence of CD31 (green) at day 7. Nuclei are stained with DAPI (blue). Vascularized areas are indicated by pink arrows. Scale bar = 100 μm. Reprinted with permission from ref (67). Copyright 2016 Elsevier.
Polymers and Polysaccharides
A biocompatible wound dressing for MRSA in diabetic foot ulcers was recently presented by Balcucho et al. (68) They combined polycaprolactone and copper oxide NPs (191 nm) to obtain an active film able to totally inhibit MRSA in 24 h. Polycaprolactone flakes, dissolved in butanol and chloroform, were mixed with a powder of CuONPs and subsequently dried in a Petri dish. The polymer is used as an immobilization matrix for CuONPs and as a substrate for biocompatibility and antimicrobial activity tests. The material is FDA approved for therapeutic agents release, hemo-compatible (red blood cell breakage less than 5%), and stable to thermal stress, but as a side effect the fibroblast activity results in vitro were reduced of 20%. Tang et al. (69) demonstrated that CuNPs can be stabilized as a powder for several months in air if prepared using a biocompatible polyelectrolyte: polyethylenimine (PEI). PEI-stabilized CuNPs were embedded in agar and deposited as a film. The substrate (2 × 1 cm) incubated with a bacterial suspension (E. coli, 2 mL, 9.0 × 108 CFU/mL) demonstrated high bacterial killing efficiency for 12 h with nearly no colony-forming units (CFU) found.
Chitosan is a linear polysaccharide known for its biocompatibility, easy biodegradability, and antimicrobial activity. When chitosan is combined with CuNPs (CCNC), the properties of the building blocks can be synergistically summed, and the resulting material will have improved ability in wound healing. (54) In rats, CCNC composites generate relevant wound contraction and fast hair coat regeneration. CCNC is composed of a mixture of colloidal chitosan solution (10%) and 50 nm CuNPs (0.3%). As shown in Figure 3, the wound contraction % in vivo is higher for CCNC than for chitosan alone starting from day 3 until day 14.
Figure 3
As expected, VEGF is found to be higher in CCNC samples than in chitosan alone, meaning a more efficient angiogenesis. The inflammation markers such as TGF-b1 and IL-10 initially increase for monocytes and macrophages because of the inflammatory activity of the chitosan. Later, the pro-inflammatory cytokines are lower if CCNC is applied with respect to chitosan alone, since the copper attenuates the inflammation process. (64)
The effective antimicrobial activity of CCNC was demonstrated in vitro by Jayaramudu et al. (70) against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria. The inhibition zone test showed that the concentration of copper determined the effectiveness of the substrate (800–400 μg/mL).
Hydrogel Copper Nanocomposites
Hydrogels are three-dimensional polymer nets characterized by their abilities to imbibe aqueous solutions (water absorption capacity up to 10 g/g) and to be arranged in different shapes such as patches, gels, ointments, and films. Hydrogels can encapsulate nanomaterials, drugs, or active biomolecules and trigger on-site controlled release. They are usually biocompatible and suitable for a wide range of medical applications, among which are the smart design of engineered tissues, wound tissues, medicament patches, and contact lenses. (71)
Vukovic et al. (72) prepared a hydrogel based on 2-hydroxyethyl acrylate and different concentrations of itaconic acid. The dried samples, immersed in a Cu2+ solution for 24 h, loaded the ions inside the gel. A following reduction induced the formation of CuNPs. The release profile and the antimicrobial activity are shown for incorporated copper(II) ions (CIx) and for reduced copper substrates (CRx) in Figure 4.
Figure 4
Figure 4. Upper graphs: Ratio between the weight of swollen hydrogel at time t and the weight of swollen hydrogel at equilibrium state. Lower graphs: Antibacterial activity of the hydrogels against E. coli, C. albicans, and S. aureus (itaconic acid concentration is varied). Reprinted with permission from ref (72). Copyright 2015 Elsevier.
Mt/Me is the fractional ion release, reported in Figure 4 versus time. The loaded substrates rapidly release the copper ions in the first hour—more rapidly with increasing concentration of itaconic acid. The CuNPs substrates, in contrast, exhibit a slower release profile and with the opposite trend: as the itaconic acid content increases, the release rate decreases. The authors suggest that the increased density of the substrate influences the slower release from the reduced substrate. The antimicrobial activity has been tested in vitro on E. coli, S. aureus, and C. albicans, highlighting a reduction in bacteria and fungi population starting from the second hour, and almost completely after 24 h.
Villanueva et al. (73) combined a starch hydrogel with CuNPs coated with silica. The silica was shown to improve the stability of the NPs, avoiding the fast release oxidation of metallic copper to the blue ion Cu2+. They were not able to detect the amount of ion released after 24 h, claiming it was too low. Different doses of NPs per grams of gel were tested for antimicrobial activity against both Gram-positive and Gram-negative bacteria via an inhibition zone test. The antibacterial effect was recorded for all concentrations tested, and specifically it increased with the NPs concentration (0.36–1.27 mmol of Cu per gram of gel).
The hydrogel prepared by Qui et al. (74) showed peroxidase-like activity; i.e., it could convert hydrogen peroxide into ROS, which are toxic for bacteria. The hydrogel was obtained from Cu(NO3)2 and l-aspartic acids (l-Asp), resulting in a network of fibers with nanometric diameter (50–70 nm). The peroxidase activity was demonstrated by observing the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) caused by hydrogen peroxide and with a terephthalic acid assay. The acid captures radicals from the oxidation reaction and generates fluorescent hydroxyterephthalic acid (TAOH). Interestingly, the substrates were applied directly on rat wounds that were infected with drug-resistant Gram-positive Staphylococcus aureus (DR-S. aureus) and Gram-negative Escherichia coli (DR-E. coli). Results indicated that the Cu-hydrogel + H2O2 can kill almost all the bacteria in the wound, performing much better than hydrogel alone or H2O2 alone. This strong antibacterial activity can be imputed to synergic effects between (i) CuNPs that exert their inhibition activity against bacteria according the mechanisms explained before (see Antimicrobial Action of Copper Nanoparticles) and (ii) the transformation of low levels of hydrogen peroxide in ROS that results in high toxicity for drug-resistant bacteria. Moreover, wound healing is evidently improved from a visual inspection and from histological analysis of skin tissue.
CuNPs in Natural Fibers
A wound dressing can benefit in terms of durability and resistance when a resilient material is used. Fibers, cellulose, and tissues are traditionally used in topical medicaments and wound protection. Exploiting the combination with nanomaterials and other material as fibers could significantly enhance the functionality of such dressings. (75) Bacterial cellulose is a peculiar polymer with a structure composed of nanofibers of cellulose arranged in a network. The name derives from the fact that it is synthesized by bacteria, which allow high purity and strength without the necessity of refining treatments. (76) For its biocompatibility, cost-effectiveness, ability to hold/release water, and rheological properties, bacterial cellulose appears to be a good candidate for wound dressing design. (77) Concerning CuNP composites as antimicrobial materials, nanocellulose is used as a substrate for copper-hydrogel deposition or as a surface to directly grow CuNPs. A polysaccharide-based hydrogel on cellulose with in situ-prepared CuNPs (20–50 nm) was recently described by Gutierrez et al. (78) An alginate/bacterial cellulose hydrogel was 3D-printed, adding a reducing agent dropwise and producing incorporated CuNPs. Briefly, alginate beads were prepared by ionic cross-linking and by their incubation with a divalent ion salt. Then, copper nitrate was added and reduced by the dropwise addition of NaBH4. This material was finally 3D-printed on bacterial cellulose. The 3D structures demonstrated antimicrobial activity against E. coli and S. aureus strains in vitro. Similarly Chowdhury et al. (79) soaked CuNPs in oil palm empty fruit bunch (EFB), which has no antibacterial activity per se but acquires an evident antibacterial and antifungal activity if copper is present. Both E. coli and S. aureus were killed after 1 h of exposure.
Cellulose nanofibrils oxidized with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) widen the possible uses of cellulose-based nanocomposites. For the preparation, pulp of Norwegian spruce is subjected to defibrillation by a TEMPO-mediated oxidation and mechanical disintegration. (80) The material is finally homogenized and poured on a Petri dish to form a 10 μm film. It is demonstrated that this material is particularly prone to adsorption of metal oxides, dyes, and other active species. Valencia et al. (80) grew Cu2O NPs on TEMPO-oxidized cellulose nanofibril (TOCNF) exploiting the reduction capabilities of the aldehyde groups present in TOCNF to produce copper in the metallic form. The obtained substrate was able to remove efficiently a dye from an aqueous solution and effectively inhibit Gram-negative (E. coli) and Gram-positive (Listeria innocua) bacteria.
Another very common material used as substrate for wound dressing that is suitable for incorporating NPs for generating antimicrobial activity is cotton fabric. Its popularity derives from the fact that cotton fabrics possess excellent properties, such as biodegradability, softness, hygroscopicity, and regeneration properties. It is possible to incorporate CuO NPs to generate a bactericidal coating against Gram-negative and Gram-positive pathogens. (81) Combination with an extract of Sida acuta leaves can promote a more efficient activity in killing bacteria against E. coli, P. vulgaris, and S. aureus. (82)
Natural cotton fibers can be converted into carboxymethyl cotton fibers with chloroacetic acid for CuNPs grafting. (75) Briefly, anionic cotton is prepared and immersed in a solution of copper sulfate. The chelated ions are reduced and generate CuNPs. The metal NP-coated cotton substrate gains efficient antimicrobial activity against the MDR bacterium A. baumannii. In comparison with just copper ions, the NP-coated cotton substrate is efficient at a total copper concentration that is about 20-fold lower. This was demonstrated by a zone of inhibition assay and a growth inhibition assay. These tests also showed a more pronounced antibacterial activity of the copper substrate in comparison with a commercial one and the analogous silver substrate (Figure 5). These last two substrates are proven to release metal ions in the medium, while only traces of copper ions are detected from the copper substrate in the medium. From a test of compatibility with mammalian cells, copper-coated substrate allows the growth of cells, differently from Ag substrates, probably due to an uptake of copper into these cells. (75)
Figure 5
Figure 5. Live–dead staining at laser scanning confocal microscopy are in picture 1, 2, and 3 (red cells = dead, green cells = dead, fibers = red for autofluorescence). SEMs of copper–cotton substrates are in picture 4, 5, and 6. Graph A: Antimicrobial activity against A. baumannii at different times. Graph B: A direct comparison among Cu- and Ag-coated cotton substrates and a commercial silver wound dressing, Acticoat. Graph C: Plot showing about 3-log kill for Cu-cotton samples in the presence of A. baumannii. Reprinted with permission from ref (75). Copyright 2011 John Wiley and Sons.
Marković et al. (83) investigated the release of Cu2+ ions from a similar nanocomposite into physiological saline solution when changing the amount of copper. Cotton fibers were treated with (3-aminopropyl)triethoxysilane (APTES) for the complexation reaction with copper and subsequently reduced to NPs. Despite the different Cu content between the samples (from 117 μmol/g to 26 μmol/g), the release of copper ions in the first 9 h was comparable (1.5 μmol/g). Both substrates can effectively inhibit the antibiotics-resistant bacteria E. coli, K. pneumoniae, and S. aureus, while only the sample comprising more copper can ensure the reduction of C. albicans. On the other hand, the extract of the more concentrated sample was toxic for skin cells, reducing their viability to 80%. (83)
CuNPs-Assisted Photothermal Ablation of Microbes
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Photothermally active NPs can convert light into heat. (8485) Under light irradiation with a specific wavelength, these NPs can generate a local and rapid increase of temperature. This approach can be exploited for fast and efficient bacteria eradication, even those resistant to conventional drugs. It could be a great advantage for some specific and precise applications since it can be exogenously triggered on demand. Plasmonic NPs or inorganic, carbon-based materials, chalcogenides, and metal oxide NPs are just some of the materials that can produce photothermal activity. CuSNPs behave like a semiconductor material that strongly absorb in the NIR region (mainly 900–1200 nm) by promoting electrons to the valence band and exerting heat emission by their relaxation. (86,87) CuSNPs are cheaper than noble metal NPs, and the thermic effect is conveniently combined with the intrinsic chemical antibacterial action generated from the ion release and ROS production. (88) Moreover, CuNPs combined with photothermal effect are demonstrated to be effective in enhancing tissue regeneration. In vitro studies (89) show that Cu2S nanoflowers incorporated in biopolymer fibers exhibit controllable photothermal performance under irradiation, support the spreading and the regeneration of human dermal fibroblasts, and accelerate the migration of endothelial cells. Similar results were shown in vivo by Zhou et al., (90) where they combined the CuS properties with the advantages of hyaluronic acid hydrogel. The increase in temperature achieved upon 808 nm irradiation of different concentrations of CuNPs (10, 20, 50, 100, and 200 μg/mL) went up to 50 degrees above the room temperature. Collagen deposition and regulated expression of VEGF on wounds on rats demonstrated the improvement in wound healing caused by the irradiated CuS-hydrogel with respect to hydrogel alone, irradiation alone, and CuS-hydrogel alone.
Few investigations on the antimicrobial photothermal treatment using CuNPs, CuS NPs, or CuS nanodots, alone or in hydrogels, are reported in the literature. Generally, the photothermal treatment exerts an intense antimicrobial activity, directly dependent on the concentration of the particles and the laser power. In the work of Tao et al., (55) CuNPs chelated with N,N-bis(acryloyl)-cystamine (BACA) were radically polymerized with methacrylate-modified gelatin. A 3D network was generated where the closeness of CuNPs produced a localized surface plasmon with resonance at 808 nm. At this wavelength, the CuNPs-hydrogel can induce a temperature increase by up to 40 degrees in 4 min, depending on the laser power and the copper concentration.
The CuNPs hydrogel, even with irradiation, is compatible with the proliferation of endothelial cells and does not produce any toxic effect, well mimicking the extracellular matrix. In vitro experiments demonstrate the ability of CuNPs hydrogel to kill both Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria with no irradiation, and even more when irradiation is on. CuNPs hydrogel deposited on rat chronic wounds infected with S. aureus and regularly irradiated demonstrated a clear acceleration of the healing, reduced inflammation, and promoted angiogenesis (Figure 6). (55) Due to the smart design of the material, a photothermal effect from CuNPs has been obtained, despite the usually low thermal emission of CuNPs (metallic or oxides) compared to CuS.
Figure 6
Figure 6. (A) Steps of healing of infected wounds in mice on days 0, 2, 4, 8, and 14. (B) Wound area closure (%) at different times points. (C) Bacteria from the wound tissues on LB agar plates (a: control; b: hydrogel; c: hydrogel + laser; d: Cu-NP-embedded hydrogel; e: Cu-NP-embedded hydrogel + laser). (D) Log of total bacterial CFU on the LB agar plates. Reprinted with permission from ref (55). Copyright 2013 Royal Society of Chemistry.
A paper by Qiao et al. (91) compared the performance in the synergistic antibacterial effect under irradiation of CuSNPs and Cu nanodots (NDs) with and without irradiation. Drug-resistant Gram-negative bacterial ESBL E. coli and MRSA were affected in vitro from all four situations, but the antimicrobial effects of CuSNDs plus NIR laser irradiation was particularly relevant. Indeed, the researchers detected a higher ROS production for the ultrasmall CuSNDs (∼6 nm) because of the corresponding higher photodynamic conversion effect. Interestingly, the CuSNPs plus irradiation and CuSNDs with no irradiation produced similar effects in both strains (Figure 7). The morphological changes evidenced from TEM images of treated microbes showed damages after CuSNPs plus laser or Cu NDs treatments such as membrane lysis and loss of integrity. The membrane permeability increases with CuSNDs plus laser treatment.
Figure 7
Figure 7. Upper panel: Photos and relative survival rates of ESBL E. coli (up) and MRSA E. coli (down). In the graphs The amount of bacteria is reported vs the concentration of NPs. Down panel: TEM images of ESBL E. coli and MRSA for CuS NPs, CuS NDs with and without laser irradiation (2.5 W/cm2, 10 min). Reprinted with permission from ref (91). Copyright 2019 American Chemical Society, with Creative Commons Attribution (CC BY) license.
The CuSNPs combined with light treatment are therefore an efficient tool for cell disruption, making them particularly suitable for synergistic treatment with an even wider field of application. The antimicrobial activity generated in the photothermal treatment can coexist with other treatments, generating an effective and multifunctional therapy. Chitosan-coated hollow CuS can be used in a photothermal immunotherapy approach, where they reduce the tumor growth and stimulate the release of tumor antigens. (92) Yin et al. (93) used CuSNPs for decorating upconverting NPs covered with NaYF4:Mn/Yb/Er and Methylene Blue-doped silica to improve the efficiency of energy transfer. They combined photodynamic and photothermic therapy for the treatment of MDR bacteria infection. The antibacterial activity for both S. aureus and E. coli bacteria under NIR light was assessed in vitro, reaching 50% of viability with 150 μg/mL and 20 min of irradiation. Using a quite high concentration of particles (300 mg/mL) and an irradiation of 20 min, the bacteria were completely killed.
CuNPs as Antiviral Agents
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Pharmaceuticals usually need to be specifically designed for a virus in order to prevent infection. In this regard, (94,95) NPs have the potential to be employed as cost-effective wide-spectrum antiviral agents due to their mechanisms of action. (96) Gold and silver NPs have been profusely studied in this field, while less is known about CuNPs’ behaviors. Hang et al. (97) suggested a specific virus inhibition of CuNPs by a direct binding with virion surface that blocks the interaction with cell receptors. Otherwise, several authors suggested that the antiviral activity of CuNPs is associated with an antibacterial-like mechanism: “contact killing” (i.e., structure damage), oxidative stress, DNA degradation, and inhibition of activity. (96,98−100) The CuNPs can directly bind to viruses and damage the capsids by physical or chemical interactions caused by the generation of toxic species. (96,98−100) The release of copper ions from NPs may support all the mentioned effects, since Cu ions have a direct antiviral activity. (98,101) The several properties of CuNPs highlighted in in vitro and in vivo investigations show the importance that this material can have in antiviral coatings and treatment. Copper(II) chloride is demonstrated to be effective in inhibiting dengue virus type-2 at a concentration of 0.13 μg/mL without any toxicity for Vero cells. The activity is imputed to copper ions interacting with the cysteine residues on the surface of the protease. (100) Most recently, CuNPs attracted attention because of their potential employment in face masks. Copper oxide-impregnated masks filtered >99.85% of human influenza A virus (H1N1) and avian influenza virus (H9N2), and no traces of the viruses were recovered from the copper-treated masks after 30 min. (99) Inspired by this, Escoffery et al. (102) presented a CuNPs-infused mask for the neutralization of SARS-CoV-2. They produced CuNPs from a dime using hydrogen peroxide, vinegar, and salt, soaked the solution into a cotton fiber mask, and showed the reusability of the substrate. More studies are required in this direction, but the increasing importance of CuNPs should be noted in the health sector. Furthermore, some in vitro investigations evidence the various actions that CuNPs can exert on the virus, among them infection inactivation by avoiding the entrance of the virus in cells, disruption of the virus, or inhibition of their replication.
An in vitro study demonstrated by microscopy images that Au/CuS core/shell NPs can rapidly inactivate norovirus GI.1 virus-like particles. (19) Tavakoli and Hashemzadeh (95) analyzed the effect of CuONPs on Vero cells after they were infected with herpes simplex 1. The inhibition of the infection was confirmed via quantitative PCR and Median Tissue Culture Infectious Dose (TCID50). The maximum nontoxic concentration of CuONPs (100 μg/mL) led to about an 83% inhibition rate (similarly to the antiviral activity of acyclovir at 20 μg/mL), demonstrating a good ability to block the proliferation of the infection.
Hang et al. (97) presented a study in which Cu2O NPs were evaluated to both terminate and avoid viral infections. This approach can be of particular interest for certain viruses which are persistent and can lead to relevant consequent pathologies. Hepatitis C virus (HCV) is an interesting example. Indeed, HCV is a major public health problem since it becomes chronic in 80% of cases and can lead to hepatocellular carcinoma or hepatic cirrhosis. The current treatments are quite toxic and often can lead to virus resistance. The results showed that Cu2O NPs play a role in the binding and the entry of the virus in hepatic human cells. They can inhibit the infection at a concentration of 2 μg/mL, more efficiently than chloroquine and a specific antibody. If applied at different time points (before and after the infection), the antiviral activity changes: Cu2O NPs can inhibit the virus only in an early stage; after 2 h they already lose their activity. They probably interact with the virion surface, avoiding interaction with the cell receptor. Interestingly, a study (94) reported an in ovo investigation to assess the employment of CuNPs as antivirals. CuONPs, prepared with fruit extract of Syzygium alternifolium, were used against Newcastle Disease Virus (NDV)-infected chicken eggs at 25, 50, and 100 μg/mL of CuO NPs. The presence of the virus was detect by the hemagglutination (HA) test. At a concentration of 100 μg/mL, CuO NPs demonstrated a strong inhibitory activity, preventing the growth of the virus in the allantoic fluid of the eggs. In these conditions, the viability of the egg is 100%, suggesting the potential of the treatment. (94)
Biodistribution, Toxicity, and Persistence of CuNPs
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Most of the investigations on CuNPs consider their impact on cell viability by analyzing a range of concentrations of copper in order to elucidate their potential toxicity profile. In general, in addition to the amount of copper, the matrix or the molecules surrounding the NP contribute positively or negatively to the cytotoxicity. An in vitro study on the dissolution kinetics of CuNPs showed that the surface functionalization of CuNPs defined the rate of ion release due to modulated oxidation, (103) affecting their cytotoxicity on human type II alveolar epithelial cells. PEG-CuNPs dissolve faster than other functionalized with thiolated acids. The dissolution rate decreases with the increasing concentration of CuNPs (hypothetically because of the agglomeration of particles), and the maximum dissolution amount is reached in about 8 h. (103) Almost 100% of the cells remained alive after 4 h from the treatment for concentrations up to 50 μg/mL, while at 100 μg/mL a significant reduction was recorded (Figure 8). After 24 h, a decrease in viability was evident, depending on the increased concentration of copper.
Figure 8
Figure 8. Cells viability normalized on the control vs concentration (logarithmic) of CuNPs at (a) 4 h and (b) 24 h. Lines and colors refer to different surface ligands on NPs (8-mercaptooctanoic acid (MOA), 12-mercaptododecanoic acid (MDA), and 16-mercaptohexa-decanoic acid (MHA)). Reprinted with permission from ref (103). Copyright 2009 Royal Society of Chemistry.
CuNPs in bioactive glasses had no significant toxicity toward fibroblast cells and human mesenchymal stem cells when applied in vitro at concentrations of 100, 10, and 1 μg/mL. (104) HUVEC viability in vitro was similar in the presence of CuNPs prepared with A. saralicum extract (62) or F. vulgaris extract. (53) It was above 80% even up to 1000 μg/mL and definitely higher compared to copper sulfate, suggesting the importance of the nanomaterial composition. Similar results were obtained with cashew gum-stabilized CuNPs on murine macrophages and murine fibroblast cells (46) and with CuS hydrogels after 48 h on mouse embryonic fibroblasts, where the proliferation results were even more promoted. (90)
A prior evaluation of the impact of CuNPs on the functionality of organs and the description of their biokinetics is pivotal for the translation of nanomaterials to the clinical practice. (105−109110) The information present in the currently available literature does not describe a complete assessment regarding the persistence and accumulation of CuNPs in the body. On the other hand, CuNPs have some advantages with respect to other non-biodegradable metals (i.e., gold). Indeed, they should easily dissolve in biological fluids and be metabolized or excreted. It should be noted that a comprehensive knowledge of the overall clearance process of CuNPs is more difficult with respect to other metals because of the natural presence of copper in living organisms.
Yin et al. followed the accumulation and clearance in mice of copper ions in different oxidation states after injection of glutathione complex with Cu(I) and the oxidized glutathione disulfide complex with Cu(II) (111) (Figure 9). The complexes are excreted mostly from the body, with more efficient renal clearance for the first one. Most of the complexes that are not expelled via urine and feces accumulates in the liver, 13% ID and 27.5% ID, respectively. The difference in accumulation can be attributed to the valence of the ions, suggesting that Cu(II) complex forms strong bounds with protein and remains in the liver more than Cu(I) complex. Furthermore, fluorescence measurements on in vitro samples demonstrate that the Cu(I) complex is fast oxidized to Cu(II), in the first 4 h. Introducing radioactive copper in Cu(I) complex, positron emission tomography on treated mice shows that the metal moves to kidney and then to the bladder rapidly in the first 30 min. It persists mostly in the bladder for the first hours, confirming the rapid clearing of the metal complex to urine.
Figure 9
Figure 9. (A) Copper in the urine of mice at different times post injection. (B) Biodistribution of Cu(I)-GSH and Cu(I) complex (Cu(II)-GSSG). (C) Liver to urine ratios of the two complexes at 24 h. (D) Fluorescence intensity of the complexes (black is Cu(I) complex, red the Cu(II) complex). (E) Time dependence of copper distribution in kidneys and bladder. Reprinted with permission from ref (111). Copyright 2017 The Authors, published open access by MDPI under Creative Commons Attribution (CC BY) license.
Yang et al. (112) compared the renal clearance and degradation of 2 nm Glutathion-CuNPs and their released products (Cu(II) complex) after injection in mice. Approximately, the 78.5% ID of Glutathion-CuNPs is excreted through the urine in the first 24 h while only the 22% ID of the Cu(II)complexes is found in the urine. Free ions of copper are demonstrated to bind with caeruloplasmin and hephaestin, remaining easily trapped in the liver. Glutathione reduces this affinity because it creates a zwitterionic shield that influences the charges interaction. Using radioactively marked glutathione-CuNPs, it is demonstrated that they do not bind to serum proteins but they undergo to a gradual dissociation in biological fluids, producing Cu(II)complexes, which partially bind to serum protein. This means that the initial distribution of copper in tissues is due to Glutathione-CuNPs, and in the following 24 h it is strongly influenced by the formation of the ion complex. After 24 h about 30% ID of Cu(II) complex is in the liver and up to 0.9% ID is present in kidneys, lowering to 0.6 in brain and 0.3 in lungs. (112)
Liang et al. (113) investigated the renal clearance of glutathione-CuNPs in mice after intravenous injection of 1.8 μg/mL. Specifically, glutathione CuS nanodots (GSH-CuS NDs) are directly revealed in urine samples exploiting their intrinsic NIR absorption (700–1300 nm). In accordance with previous studies, GSH-CuS NDs are found in urine 1 h after the injection reaching the 54.6% ID at 24 h after the administration (Figure 10). The possibility to record their presence in urine by NIR suggest that they are expelled intact.
Figure 10
Figure 10. Upper panels: Renal clearance and biodistribution studies of GSH-CuS NDs. (A) Absorption spectra of urine samples before and 1 h after the injection. (B) Amount of Cu excreted in urine. (C) Biodistribution of GSH-CuS NDs at 24 h post-injection. D) MR images of GSH-CuS NDs enhanced (from a to j: pre-injection and 30 s, 1 min, 2.5 min, 5.5 min, 10.5 min, 30.5 min, 1 h, 2 h, and 24 h post-injection signal enhancement in heart (B) and bladder (C) caused by GSH-CuS NDs. Reprinted with permission from ref (113). Copyright 2013 Royal Society of Chemistry.
The in vivo distribution of GSH-CuS NDs is furthermore studied by magnetic resonance imaging, taking advantage of the magnetic properties of copper. After injection, a signal enhancement is detected in the heart, slowly disappearing after 2 h, meaning that in that range of time, GSH-CuS NDs can freely circulate in the vessels without being catch by the reticuloendothelial system. At the same time, the signal intensifies gradually in the bladder region, demonstrating that GSH-CuS NDs are filtrated by the kidneys. After 24 h only the 7.7% ID and 3.3% ID accumulate in liver and kidneys, respectively, which is significantly lower compared to the other works mentioned. This result could be attributed to the smaller size of NPs, suggesting that the ultrasmall NPs undergo to rapid renal clearance, faster than bigger NPs, reducing the exposure of the organs to dissociated copper ions. Consistently, to other metals like gold, it is known that the renal clearance efficiencies depends on size, together with shape, charge, and composition. (114) The supposed threshold for renal clearance of intact metal-based NPs is around 6 nm. (115) The work of Han et al. (116) confirmed this concept, presenting the distribution and metabolism of ultrasmall copper selenide NPs (Cu2–xSe). The 2 nm NPs, after being injected in mice intravenously at a concentration of 10 mg/kg, are eliminated mostly in urine and feces in 6–12 h (29.2% and 36.7%, respectively). In the first 2 h, Cu2–xSe are found located mostly in kidneys (12.1 μg/g of tissue), decreasing then at 72 h (2 μg/g of tissue), confirming the ability of this particles to pass through kidneys and to be excreted rapidly by the urinary system. Concerning the other organs, the lungs accumulation is similar to the kidney one, followed by the spleen and the heart. Liver is an exception, in which the copper content reaches the maximum of 20.8 μg/g of tissue after 4 h from the injection. Interestingly, the copper released was measured in vivo in a range of time, thanks to a fluorescent probe specifically designed to activate in the presence of Cu2+. After accumulation in the liver, fluorescence diffuses to intestines and spleen, for becoming weaker after 8 h in the liver and more intense in the intestines. The fluorescence disappear after 72 h, demonstrating that after releasing copper in the liver, it is metabolized to intestines and totally eliminated with feces after 72 h (Figure 11). (116)
Figure 11
In order to elucidate the influence of the copper release to organs in mice, the authors characterize several proteins in the liver that are involved in copper storage and transport. As instance, ATP7B protein usually acts for copper trafficking and export of copper in excess out of the cell, regulating the copper content in the bile. Its activity is increased at 12 and 48 h after the injection and became normal again at 72 h. This evidence is consistent with degradation of Cu2–xSe NPs and with a consequent increase of ion that makes the liver cell decrease the uptake and increase the elimination of copper ions. Importantly, the histological analysis on major organs do not show any cell damage at day 1, 3, 10, 20, and 28 (dose: 10 mg/kg), highlighting the very low toxicity of the treatment.
No damage in organs is found as well if 120 nm CuS nanoplates are injected in mice at a concentration of 5.5 mg/kg. (117) In this work, the concentration of copper in organs is measured via inductively coupled plasma atomic emission spectrometer and subtracted to the normal content of copper in the organs. The level in liver and kidneys increases to 1.6 and 0.9 μg/g at 4 h after injection and decreases again at 48 h. Lungs and liver follow a comparable trend while the spleen reaches 2.4 μg/g after 30 min, to decrease rapidly after. Overall the findings are similar to what described in the work of Han et al.: (116) most of the copper is rapidly excreted via urinary system and feces with no toxic effect on organs after injection. Considering the acute toxicity, the maximum tolerated dose is calculated to be 8.66 mg/kg and the medial lethal dose is 54.5 mg/kg.
Dey et al. (118) determined the biodistribution of about 50 nm copper oxide NPs, comparing two different synthetic ways: chemical and green with Azadirachta indica. They demonstrated that even for lower doses of CuNPs (1–0.1 mg/kg), the accumulation in liver and spleen is significant and increases by increasing the injected amount of CuONPs. Interestingly, almost no toxicological effect was noticed only with the mice treated with the green NPs from the histopathological images on organs after 15 days of treatments. This confirms that the conjugation of the NPs is a relevant factor for modulating the toxicity. Hepatotoxicity is also found on mice orally treated with up to 6.5 mg/kg of 40–60 nm CuNPs in a diet of 4 weeks. (119) Compared with a copper carbonate diet, CuNPs are better adsorbed in the digestive tract than copper from the other source, in accordance with a lower copper excretion in feces and urine. These results may suggest that a long-lasting treatment with CuNPs orally administered can expose the digestive system to a stress that can bring to relevant tissue damage. Lei et al. (120) also detected liver damage in mice orally treated with a shorter regime but with a higher dose of NPs (5 days, 200 mg kg–1 d–1 of CuNPs). Furthermore, Cholewinska et al. (119) noticed a significant accumulation of copper in the brain of mice after a 4 weeks CuNPs diet, higher with respect to the carbonate-based diet. The CuNPs are, hence, able to move from the digestive system to blood, cross the blood–brain barrier, and significantly accumulate in organs. The potential adverse effects of CuNPs accumulation in rat brain were recently studied by Fahmy et al. (121) They monitored specific oxidative stress parameters and acetylcholinesterase (AChE) activity after intravenously injecting rats for 2 days with 15 mg/kg of 14 nm CuNPs. The quantification of copper in the different areas of the brain reveals an increase in all brain areas, except the medulla and mid brain. Hippocampus contains 0.04 mg of copper per grams of tissue, which is the highest value among all areas. Overall, significant changes in oxidative stress are detected together with inflammation and changes in the behavior of rats (decrease in exploring motion up to 54%). (121) These results are coherent with a precedent work (122) where, alternatively to intravenous injection or oral exposure, CuNPs are administered via intranasal doses. A few microliters of 25 nm CuNPs at concentrations up to 40 mg/kg are instilled in the naris of the mice three times over a week. In addition to oxidative stress, CuNPs seems to cause lesions in olfactory cells in hippocampus and influences the nervous system. (123) If the dose is reduced to 1 mg/kg, no lesion is observed, neither in the brain or liver. (124)
The effect of a long-term exposure to copper as ion generates a not negligible adverse effects in the brain. A study from Pal et al. (125) described long-term copper toxic effects in rats after injection of copper lactate solution (0.15 mg Cu/100 g BW), daily for the period of 90 days. They observed brain swelling and increased number of astrocytes, accompanied by impaired spatial memory and neuromuscular coordination. Accordingly, Kardos et al. (126) found that the free excess of copper accumulates close to the cerebral cortex and hippocampus. It is supposed that a long-term exposure to an excess of copper ions can be caused by a high fat diet. (25) Concerning the long-term effects of an excess of copper ion in the body, it is important to notice that only a few works have investigated CuNPs. Copper ions are reported from several studies to have an impact in the immune system, in ovaries, and in nervous system.
Relevant is the involvement of copper in the development of Alzheimer’s disease. The metal has high affinity for the β-amyloid peptide, altering the structure, enhancing the agglomeration and formation of plaques, which are the cause of the disease. (25) Not only copper as ion has this effect, but also environmental CuONPs can be associated with the promotion of Alzheimer’s disease. (127) In a recent in vitro study, two human cell lines (human neuroblastoma and human neuroglioma) have been incubated for 1 day with a quite high concentration of CuONPs (100 μM). By monitoring the pathological features connected with Alzheimer’s disease, an increase in primary components of β-amyloid plaques, probably due to oxidative stress, has been observed. This suggests the possible implication of CuONPs in the development of Alzheimer’s disease, even if, at the moment, in vivo confirmations are still missing. Zhang et al. (128) recently investigated in vivo FexCuySe NPs for the treatment of Alzheimer’s disease. The NPs, functionalized with penicillamine, show a promising ability of inhibition of β-amyloid 42-monomer aggregation and of the disaggregation of β-amyloid fibrils. (128)
Inhalation of CuNPs is reported to cause lung inflammation, increasing the level of total proteins in bronchoalveolar fluids. (129) Furthermore, after 1 week of exposure to 5 mg/kg, histopathological analysis revealed a certain degeneration of lungs, fibrosis, and granuloma. (130) When 25 nm CuNPs were coated with chitosan and administered via nasal instillation and about 30 μg of copper was deposited per mouse (via tracheal incision), the inflammation was increased with respect to treatment with CuNPs without chitosan. The polysaccharide is responsible of this effect since it has severe proinflammatory effects on lung tissues (131) and it adheres well to the mucus, prolonging the exposure to metal and avoiding the clearance. (132)
Table 2. Summary of Biodistribution, Toxicity, and Persistence Investigations on CuNPs
| authors | toxicity and persistence | administration |
|---|---|---|
| Shi et al., 2017 (103) | 100% of human type II alveolar epithelial cells were alive 4 h after the treatment for concentrations up to 50 μg/mL, while at 100 μg/mL a significant reduction was recorded. | in vitro |
| Zheng et al., 2017 (104) | Viability was above 80% up to 1000 μg/mL for human mesenchymal stem cells. | in vitro |
| Amorim et al., 2019 (46) | Cashew gum-stabilized CuNPs on murine macrophages and murine fibroblast cells, above 80% even up to 1000 μg/mL. | in vitro |
| Zhou et al., 2020 (90) | CuS hydrogels after 48 h on mouse embryonic fibroblasts, above 80% even up to 1000 μg/mL. | in vitro |
| Yin et al., 2017 (111) | GSH-CuNPs persisted mostly in the bladder for the first hours, with rapid clearing of the metal complex to urine. | injection |
| Yang et al., 2015 (112) | 78.5% ID of glutathione-CuNPs was excreted through the urine in the first 24 h, and 22% ID of the Cu(II)complexes was found in the urine. After 24 h, about 30% ID of the Cu(II)complex was in the liver and up to 0.9% ID was present in the kidneys, lowering to 0.6% ID in brain and 0.3% ID in lungs. | injection |
| Liang et al., 2017 (113) | After 24 h, only 7.7% ID and 3.3% ID accumulated in liver and kidneys, respectively; also detected in the heart, slowly disappearing after 2 h. | injection |
| Han et al., 2019 (116) | Ultrasmall copper selenide NPs, 10 mg/kg, are eliminated mostly in urine and feces in 6–12 h (29.2% and 36.7%, respectively). In the first 2 h, Cu2–xSe was found located mostly in the kidneys (12.1 μg/g of tissue), then decreased at 72 h (2 μg/g of tissue). | injection |
| Feng et al., 2015 (117) | 120 nm CuS nanoplates at a concentration of 5.5 mg/kg; levels in liver and kidneys increased to 1.6 and 0.9 μg/g at 4 h. | injection |
| Dey et al., 2019 (118) | Hepatotoxicity was also found on mice orally treated with up to 6.5 mg/kg of 40–60 nm CuNPs in a diet for 4 weeks. | orally |
| Lei et al., 2015 (120) | Liver damage in mice orally treated with a shorter regime but with a higher dose of NPs (5 days, 200 mg kg–1 d–1 of CuNPs). | orally |
| Cholewińska et al., 2018 (119) | Accumulation of copper in the brain of mice after a 4 weeks of CuNPs diet; higher with respect to the carbonate-based diet. | orally |
| Fahmy et al., 2020 (121) | Accumulation in all brain areas, except the medulla and mid brain; hippocampus contained 0.04 mg of copper per gram of tissue. | intranasal |
| Shi et al., 2020 (127) | Increase in primary components of β-amyloid plaques in vitro. | in vitro |
| Sandhya Rani et al., 2013 (130) | After inhalation, a certain degeneration of lungs, fibrosis, and granuloma. | inhalation |
Conclusions and Perspectives
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In summary, copper NPs are effectively promising materials in the management of infectious and communicable diseases. The antimicrobial activity of copper is widely efficient on a plethora of microorganisms, including several multi-drug-resistant ones. CuNPs can provide a joint action against pathogens that combines penetration and disruption of the microbes’ structure (governed by the shape and the size of the NPs), the intense ROS generation by CuNPs, and the generation of superoxide molecules from released copper ions. With respect to gold and silver NPs, CuNPs demonstrated comparable or enhanced antimicrobial activity associated with a lower cost (copper is about 8 time less expensive than silver) and an increased biocompatibility. Indeed, CuNPs generate copper ions in the surroundings that contribute to the normal healthy processes of the human tissues. Copper is a cofactor for metalloproteins and enzymes, and it is essential to aerobic forms of life. It can enhance the regeneration of the tissues by increasing the quality of the skin. Consequently, this evidence suggests that CuNPs are probably the best candidates for the development of the next technologies for management of infectious and communicable diseases, where these synergistic mechanisms can be of great advantage. Further studies are needed to shed light on the antimicrobial mechanism of different CuNPs in terms of chemical composition, size, shape, and biological identity. This would help to maximize the antimicrobial effect as well as to increase the health of the tissues and minimize the toxicity. Moreover, the local toxicity and the long-term effects certainly need to be considered. It should be noted that pharmacokinetics and pharmacology information for “absorption, distribution, metabolism, and excretion” (ADME) of CuNPs in living organisms have still to be comprehensively investigated together with the biosafety profiles in different vertebrate models. A few recent investigations have demonstrated that the administration pathway of CuNPs (oral, injection, tracheal deposition) dramatically influences the fate of the nanomaterial. In general, consistent and wide data are missing concerning biokinetics and biodistribution, and even less is known about long-term persistence in the body and the environment. A rational design of nanocomposites and nanostructured materials based on copper is expected to gain much more importance in the future in a variety of applications, including antimicrobial tissues and surfaces, topical treatment, antivirals, and oncology. The works reported in this Review highlight that copper exerts toxicity only if present in excess with respect to the amount that can be metabolized from the organism. For this reason, a strong control over the amount of copper injected/released is pivotal to minimize the adverse effects. Thus, slow-releasing NPs can be crucial to ensure a suitable level of copper for efficient antimicrobial activity while avoiding an overload. In this regard, core–shell NPs such as the passion fruit-like nano-architectures are of particular interest because they comprise ultra-small NPs in a biodegradable silica nanocapsule that can be modulated to control the metal release. (106,108,133,134) The toxicity of CuNPs can be also regulated by exploiting their interaction with the environment. The surface ligands of NPs and the interplay with environmental protein (protein corona) can influence the uptake in cells and the interactions with organs, giving a relevant effect in the metabolic pathways, persistence, and toxicity. (135−137) Regarding CuNPs and protein corona formation, very few works can be found. Recently, Akhuli et al. (138) investigated the interactions between bovine serum albumin and copper nanoclusters modified with tannic acid, chitosan, or cysteine, reporting that CuNPs interact with BSA without modifying its structure. Investigations on bio/nano interactions and protein corona formation are of particular interest in order to shed light on ADME and the cellular uptake. In summary, in order to unleash the full potential of CuNPs, more comprehensive investigations on their rational design as well as on their interactions with organisms are urgently demanded.
Author Information
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- Valerio Voliani - Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12-56126 Pisa, Italy;
http://orcid.org/0000-0003-1311-3349;
Acknowledgments
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This work was supported by the MFAG 2017 - ID 19852 from Associazione Italiana per la Ricerca sul Cancro (AIRC) granted to V. Voliani (P.I.).
| copper-based nanoparticles (CuNPs) | nanoparticles with a diameter between 1 and 100 nm constituted of copper or a copper-based compound |
| reactive oxygen species (ROS) | free oxygen radicals that may cause damage to DNA, RNA, and proteins, and may cause cell and microbe death |
| vascular endothelial growth factor (VEGF) | signal protein produced by cells for stimulating the process of formation of blood vessels |
| human umbilical vein endothelial cells (HUVEC) | cells derived from the endothelium of veins from the umbilical cord |
| absorption/distribution/metabolism/excretion/toxicity (ADMET) | a set of criteria to evaluate the behaviors of a therapeutics within an organism |
References
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This article references 138 other publications.
- 1Luo, G.; Gao, S. Global Health Concerns Stirred by Emerging Viral Infections. J. Med. Virol. 2020, 92 (4), 399– 400, DOI: 10.1002/jmv.25683Google Scholar1Global health concerns stirred by emerging viral infectionsLuo, Guangxiang; Gao, Shou-JiangJournal of Medical Virology (2020), 92 (4), 399-400CODEN: JMVIDB; ISSN:0146-6615. (Wiley-Blackwell)A review. The most recent outbreak of viral pneumonia in the city of Wuhan, China, which started in the middle of Dec., 2019 and now is spreading to many places in China as well as to many other countries and regions around the world, serves as an important reminder of our vulnerability to emerging viral infections. Further characterization of the isolated virus in cell culture and animal models will provide valuable information as to the underlying mol. mechanism of viral replication and pathogenesis. More significantly, identification of animal reservoir and intermediate hosts for the 2019-nCoV is crit. for intervention and prevention of the outbreak. It is of paramount importance to develop sensitive and reliable diagnostic methods for rapid detection of viral infection, including immunoassay for quantification of virus-specific antibodies. The ultimate control of emerging viral infections requires discovery and development of effective antiviral drugs and vaccines, which may take months or evenyears. However, it is possible that some of the licensed antiviral drugs for treatment of other viral infections may also have activity against the 2019-nCoV, as previously reported for MERS CoV. More importantly, isolation and cloning of virus-neutralizing antibodies from recovered patients will immediately impact on the treatment and prevention of 2019-CoV infection.
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- 3Akhavan, O.; Ghaderi, E. Cu and CuO Nanoparticles Immobilized by Silica Thin Films as Antibacterial Materials and Photocatalysts. Surf. Coat. Technol. 2010, 205 (1), 219– 223, DOI: 10.1016/j.surfcoat.2010.06.036Google Scholar3Cu and CuO nanoparticles immobilized by silica thin films as antibacterial materials and photocatalystsAkhavan, O.; Ghaderi, E.Surface and Coatings Technology (2010), 205 (1), 219-223CODEN: SCTEEJ; ISSN:0257-8972. (Elsevier B.V.)CuO nanoparticles with av. diam. of about 20 nm were accumulated on surface of sol-gel silica thin films heat treated at 300 °C in air. Heat treatment of the CuO nanoparticles at 600 °C in a reducing environment resulted in effective redn. of the nanoparticles and penetration of them into the film. While the thin films heat treated at 300 °C exhibited a strong antibacterial activity against Escherichia coli bacteria, the reducing process decreased their antibacterial activity. However, by definition of normalized antibacterial activity (antibacterial activity/surface concn. of coppers) it was found that Cu nanoparticles were more toxic to the bacteria than the CuO nanoparticles (by a factor of ∼ 2.1). Thus, the lower antibacterial activity of the reduced thin films was assigned to diffusion of the initially accumulated copper-based nanoparticles into the film. The CuO nanoparticles also exhibited a slight photocatalytic activity for inactivation of the bacteria (∼ 22% improvement in their antibacterial activity). Instead, the normalized antibacterial activity of the Cu nanoparticles covered by a thin oxide layer highly increased (∼ 63% improvement) in the photocatalytic process. A mechanism was also proposed to describe the better antibacterial activity of the Cu than CuO nanoparticles in dark and under light irradn.
- 4Labruère, R.; Sona, A. J.; Turos, E. Anti-Methicillin-Resistant Staphylococcus aureus Nanoantibiotics. Front. Pharmacol. 2019, 10 (October), 1121, DOI: 10.3389/fphar.2019.01121Google Scholar4Anti-methicillin-resistant Staphylococcus aureus nanoantibioticsLabruere, Raphael; Sona, A. J.; Turos, EdwardFrontiers in Pharmacology (2019), 10 (), 1121CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. Nanoparticle-based antibiotic constructs have become a popular area of investigation in the biomedical sciences. Much of this work has pertained to human diseases, largely in the cancer therapy arena. However, considerable research has also been devoted to the nanochem. for controlling infectious diseases. Among these are ones due to bacterial infections, which can cause serious illnesses leading to death. The onset of multi-drug-resistant (MDR) infections such as those caused by the human pathogen Staphylococcus aureus has created a dearth of problems such as surgical complications, persistent infections, and lack of available treatments. In this article, we set out to review the primary literature on the design and development of new nanoparticle materials for the potential treatment of S. aureus infections, and areas that could be further expanded upon to make nanoparticle antibiotics a mainstay in clin. settings.
- 5Merlin, C. Reducing the Consumption of Antibiotics: Would That Be Enough to Slow Down the Dissemination of Resistances in the Downstream Environment?. Front. Microbiol. 2020, 11 (January), 33, DOI: 10.3389/fmicb.2020.00033Google Scholar5Reducing the Consumption of Antibiotics: Would That Be Enough to Slow Down the Dissemination of Resistances in the Downstream Environment?Merlin ChristopheFrontiers in microbiology (2020), 11 (), 33 ISSN:1664-302X.There is no expanded citation for this reference.
- 6Zaman, S. B.; Hussain, M. A.; Nye, R.; Mehta, V.; Mamun, K. T.; Hossain, N. A Review on Antibiotic Resistance: Alarm Bells Are Ringing. Cureus 2017, 9 (6), e1403, DOI: 10.7759/cureus.1403Google ScholarThere is no corresponding record for this reference.
- 7Chatterjee, A.; Modarai, M.; Naylor, N. R.; Boyd, S. E.; Atun, R.; Barlow, J.; Holmes, A. H.; Johnson, A.; Robotham, J. V. Quantifying Drivers of Antibiotic Resistance in Humans: A Systematic Review. Lancet Infect. Dis. 2018, 18 (12), e368– e378, DOI: 10.1016/S1473-3099(18)30296-2Google Scholar7Quantifying drivers of antibiotic resistance in humans: a systematic reviewChatterjee, Anuja; Modarai, Maryam; Naylor, Nichola R.; Boyd, Sara E.; Atun, Rifat; Barlow, James; Holmes, Alison H.; Johnson, Alan; Robotham, Julie V.Lancet Infectious Diseases (2018), 18 (12), e368-e378CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)A review. Mitigating the risks of antibiotic resistance requires a horizon scan linking the quality with the quantity of data reported on drivers of antibiotic resistance in humans, arising from the human, animal, and environmental reservoirs. We did a systematic review using a One Health approach to survey the key drivers of antibiotic resistance in humans. Two sets of reviewers selected 565 studies from a total of 2819 titles and abstrs. identified in Embase, MEDLINE, and Scopus (2005-18), and the European Center for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and WHO (One Health data). Study quality was assessed in accordance with Cochrane recommendations. Previous antibiotic exposure, underlying disease, and invasive procedures were the risk factors with most supporting evidence identified from the 88 risk factors retrieved. The odds ratios of antibiotic resistance were primarily reported to be between 2 and 4 for these risk factors when compared with their resp. controls or baseline risk groups. Food-related transmission from the animal reservoir and water-related transmission from the environmental reservoir were frequently quantified. Uniformly quantifying relationships between risk factors will help researchers to better understand the process by which antibiotic resistance arises in human infections.
- 8Kaufmann, S.; Dorhoi, A.; Hotchkiss, R.; Bartenschlager, R. Host-Directed Therapies for Bacterial and Viral Infections. Nat. Rev. Drug Discovery 2018, 17, 35– 56, DOI: 10.1038/nrd.2017.162Google Scholar8Host-directed therapies for bacterial and viral infectionsKaufmann, Stefan H. E.; Dorhoi, Anca; Hotchkiss, Richard S.; Bartenschlager, RalfNature Reviews Drug Discovery (2018), 17 (1), 35-56CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and addnl. alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathol. Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial. In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with sol. factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory mols.). This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic.
- 9Sánchez-López, E.; Gomes, D.; Esteruelas, G.; Bonilla, L.; Lopez-Machado, A. L.; Galindo, R.; Cano, A.; Espina, M.; Ettcheto, M.; Camins, A.; Silva, A. M.; Durazzo, A.; Santini, A.; Garcia, M. L.; Souto, E. B. Metal-Based Nanoparticles as Antimicrobial Agents: An Overview. Nanomaterials 2020, 10, 292, DOI: 10.3390/nano10020292Google Scholar9Metal-based nanoparticles as antimicrobial agents: an overviewSanchez-Lopez, Elena; Gomes, Daniela; Esteruelas, Gerard; Bonilla, Lorena; Lopez-Machado, Ana Laura; Galindo, Ruth; Cano, Amanda; Espina, Marta; Ettcheto, Miren; Camins, Antoni; Silva, Amelia M.; Durazzo, Alessandra; Santini, Antonello; Garcia, Maria L.; Souto, Eliana B.Nanomaterials (2020), 10 (2), 292CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addn. to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-pos. and Gram-neg. bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their prodn. methods, physicochem. characterization, and pharmacokinetics together with the toxicol. risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-neg. bacteria has been highlighted.
- 10Lemire, J. A.; Harrison, J. J.; Turner, R. J. Antimicrobial Activity of Metals: Mechanisms, Molecular Targets and Applications. Nat. Rev. Microbiol. 2013, 11, 371– 384, DOI: 10.1038/nrmicro3028Google Scholar10Antimicrobial activity of metals: mechanisms, molecular targets and applicationsLemire, Joseph A.; Harrison, Joe J.; Turner, Raymond J.Nature Reviews Microbiology (2013), 11 (6), 371-384CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. Metals have been used as antimicrobial agents since antiquity, but throughout most of history their modes of action have remained unclear. Recent studies indicate that different metals cause discrete and distinct types of injuries to microbial cells as a result of oxidative stress, protein dysfunction or membrane damage. Here, the authors describe the chem. and toxicol. principles that underlie the antimicrobial activity of metals and discuss the preferences of metal atoms for specific microbial targets. Interdisciplinary research is advancing not only the authors' understanding of metal toxicity but also the design of metal-based compds. for use as antimicrobial agents and alternatives to antibiotics.
- 11Wang, W.; Li, B.; Yang, H.; Lin, Z.; Chen, L.; Li, Z.; Ge, J.; Zhang, T.; Xia, H.; Li, L.; Lu, Y. Efficient Elimination of Multidrug-Resistant Bacteria Using Copper Sulfide Nanozymes Anchored to Graphene Oxide Nanosheets. Nano Res. 2020, 13 (8), 2156– 2164, DOI: 10.1007/s12274-020-2824-7Google Scholar11Efficient elimination of multidrug-resistant bacteria using copper sulfide nanozymes anchored to graphene oxide nanosheetsWang, Wanshun; Li, Binglin; Yang, Huili; Lin, Zefeng; Chen, Lingling; Li, Zhan; Ge, Jiayuan; Zhang, Tao; Xia, Hong; Li, Lihua; Lu, YaoNano Research (2020), 13 (8), 2156-2164CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)Abstr.: Antibacterial nanomaterials have attracted growing interest for bacterial infection therapy. However, most nanomaterials eliminate bacteria either phys. or chem., which hampers their efficacy when dealing with multidrug-resistant bacteria. To overcome this, we integrated copper sulfide (CuS) nanoparticles with active graphene oxide nanosheets (GO NSs) to synthesize a superior nanocomposite (CuS/GO NC) that acts both phys. and chem. on the bacteria. CuS/GO NC was produced using a facile hydrothermal method, whereby the CuS nanoparticles grew and were uniformly dispersed on the GO NSs in situ. We found that the CuS/GO NC possesses a unique needle-like morphol. that phys. damages the bacterial cell membrane. CuS/GO NC also exhibits high oxidase- and peroxidase-like activity, ensuring efficient generation of the reactive oxygen species •OH from H2O2, which kills bacteria chem. These features endow the CuS/GO NC with excellent antibacterial capabilities to kill multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) with only a single dose. Addnl., it was found that the CuS/GO NC accelerated the healing of infected wounds in vivo owing to its good biocompatibility as well as facilitation of cell migration and collagen secretion. This study provides a new strategy to combine the phys. and chem. antibacterial modes of nanomaterials to develop more effective therapies to combat multidrug-resistant bacterial infections. [graphic not available: see fulltext].
- 12Lemire, J. A.; Harrison, J. J.; Turner, R. J. Antimicrobial Activity of Metals: Mechanisms, Molecular Targets and Applications. Nat. Rev. Microbiol. 2013, 11, 371– 384, DOI: 10.1038/nrmicro3028Google Scholar12Antimicrobial activity of metals: mechanisms, molecular targets and applicationsLemire, Joseph A.; Harrison, Joe J.; Turner, Raymond J.Nature Reviews Microbiology (2013), 11 (6), 371-384CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. Metals have been used as antimicrobial agents since antiquity, but throughout most of history their modes of action have remained unclear. Recent studies indicate that different metals cause discrete and distinct types of injuries to microbial cells as a result of oxidative stress, protein dysfunction or membrane damage. Here, the authors describe the chem. and toxicol. principles that underlie the antimicrobial activity of metals and discuss the preferences of metal atoms for specific microbial targets. Interdisciplinary research is advancing not only the authors' understanding of metal toxicity but also the design of metal-based compds. for use as antimicrobial agents and alternatives to antibiotics.
- 13Roy, K.; Sarkar, C. K.; Ghosh, C. K. Antibacterial Mechanism of Biogenic Copper Nanoparticles Synthesized Using Heliconia Psittacorum Leaf Extract. Nanotechnol. Rev. 2016, 5 (6), 529– 536, DOI: 10.1515/ntrev-2016-0040Google Scholar13Antibacterial mechanism of biogenic copper nanoparticles synthesized using Heliconia psittacorum leaf extractRoy, Kaushik; Sarkar, Chandan K.; Ghosh, Chandan K.Nanotechnology Reviews (2016), 5 (6), 529-536CODEN: NRAEE8; ISSN:2191-9097. (Walter de Gruyter GmbH)Here, we report on the novel green synthesis of metallic copper nanoparticles from copper sulfate soln. by using the leaf ext. of Heliconia psittacorum. The stability and gradual formation of copper nanoparticles during interaction with the ext. were investigated using UV-visible spectroscopy. The pattern of X-ray diffraction revealed the crystallinity and different phases of the nanoparticles. High-resoln. transmission electron microscopy was done to obtain information about the morphol. and microstructure of the green nanoparticles. The IR spectra detected org. bioactive mols. assocd. with capping and stabilization of the particle surface. The antibacterial properties of these bioengineered Cu nanoparticles were tested toward a Gram-pos. bacteria - Staphylococcus aureus - and two strains of Gram-neg. bacteria - Escherichia coli and Pseudomonas putida. The antibacterial study showed that these biogenic copper nanoparticles have potent bactericidal property toward the examd. bacterial species.
- 14Ramteke, L.; Gawali, P.; Jadhav, B. L.; Chopade, B. A. Comparative Study on Antibacterial Activity of Metal Ions, Monometallic and Alloy Noble Metal Nanoparticles against Nosocomial Pathogens. Bionanoscience 2020, 10, 1018, DOI: 10.1007/s12668-020-00771-9Google ScholarThere is no corresponding record for this reference.
- 15Poggio, C.; Colombo, M.; Arciola, C. R.; Greggi, T.; Scribante, A.; Dagna, A. Copper-Alloy Surfaces and Cleaning Regimens against the Spread of SARS-CoV-2 in Dentistry and Orthopedics. From Fomites to Anti-Infective Nanocoatings. Materials 2020, 13 (15), 3244, DOI: 10.3390/ma13153244Google Scholar15Copper-alloy surfaces and cleaning regimens against the spread of SARS-CoV-2 in dentistry and orthopedics. from fomites to anti-infective nanocoatingsPoggio, Claudio; Colombo, Marco; Arciola, Carla Renata; Greggi, Tiziana; Scribante, Andrea; Dagna, AlbertoMaterials (2020), 13 (15), 3244CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)The latest diffusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease (COVID-19), has involved the whole world population. Even if huge efforts to control the pandemic have been done, the viral spread is still continuing. COVID-19 is reported as a zoonosis jumped from bats and pangolins to humans. After infection in humans, SARS-CoV-2 is found in the nasopharyngeal and salivary secretions. The virus has also been detected in the blood plasma of infected patients. The viral spread occurs through droplets exhaled from the nose and mouth of the infected people when they breath or talk, or through droplets propelled as a dense cloud by chough or sneeze. The virus can also be delivered as an aerosol from blood plasma, through surgical procedures. Following these ways, the virus can disperse in the air, then reaching and settling on the exposed surfaces. How long the virus will survive on a surface depends on the material the surface is made from. Infection via high-touch surfaces should be prevented. Copper alloy coatings, combined with efficient hygienic/disinfectant procedures and careful surgical practice, could be helpful to health protection in dental practice and can also be adopted in orthopedic traumatol.
- 16Gawande, M. B.; Goswami, A.; Felpin, F. O.-X.; Asefa, T.; Huang, X.; Silva, R.; Zou, X.; Zboril, R.; Varma, R. S. Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis. Chem. Rev. 2016, 116, 3722– 3811, DOI: 10.1021/acs.chemrev.5b00482Google Scholar16Cu and Cu-Based Nanoparticles: Synthesis and Applications in CatalysisGawande, Manoj B.; Goswami, Anandarup; Felpin, Francois-Xavier; Asefa, Tewodros; Huang, Xiaoxi; Silva, Rafael; Zou, Xiaoxin; Zboril, Radek; Varma, Rajender S.Chemical Reviews (Washington, DC, United States) (2016), 116 (6), 3722-3811CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)The applications of copper (Cu) and Cu-based nanoparticles, which are based on the earth-abundant and inexpensive copper metal, have generated a great deal of interest in recent years, esp. in the field of catalysis. The possible modification of the chem. and phys. properties of these nanoparticles using different synthetic strategies and conditions and/or via postsynthetic chem. treatments has been largely responsible for the rapid growth of interest in these nanomaterials and their applications in catalysis. In addn., the design and development of novel support and/or multimetallic systems (e.g., alloys, etc.) has also made significant contributions to the field. In this comprehensive review, we report different synthetic approaches to Cu and Cu-based nanoparticles (metallic copper, copper oxides, and hybrid copper nanostructures) and copper nanoparticles immobilized into or supported on various support materials (SiO2, magnetic support materials, etc.), along with their applications in catalysis. The synthesis part discusses numerous preparative protocols for Cu and Cu-based nanoparticles, whereas the application sections describe their utility as catalysts, including electrocatalysis, photocatalysis, and gas-phase catalysis. We believe this crit. appraisal will provide necessary background information to further advance the applications of Cu-based nanostructured materials in catalysis.
- 17Nikolova, M. P.; Chavali, M. S. Metal Oxide Nanoparticles as Biomedical Materials. Biomimetics 2020, 5 (2), 27, DOI: 10.3390/biomimetics5020027Google Scholar17Metal oxide nanoparticles as biomedical materialsNikolova, Maria P.; Chavali, Murthy S.Biomimetics (2020), 5 (2), 27CODEN: BIOMJE; ISSN:2313-7673. (MDPI AG)The development of new nanomaterials with high biomedical performance and low toxicity is essential to obtain more efficient therapy and precise diagnostic tools and devices. Recently, scientists often face issues of balancing between pos. therapeutic effects of metal oxide nanoparticles and their toxic side effects. In this review, considering metal oxide nanoparticles as important technol. and biomedical materials, the authors provide a comprehensive review of researches on metal oxide nanoparticles, their nanoscale physicochem. properties, defining specific applications in the various fields of nanomedicine. Authors discuss the recent development of metal oxide nanoparticles that were employed as biomedical materials in tissue therapy, immunotherapy, diagnosis, dentistry, regenerative medicine, wound healing and biosensing platforms. Besides, their antimicrobial, antifungal, antiviral properties along with biotoxicol. were debated in detail. The significant breakthroughs in the field of nanobiomedicine have emerged in areas and nos. predicting tremendous application potential and enormous market value for metal oxide nanoparticles.
- 18Sánchez-López, E.; Gomes, D.; Esteruelas, G.; Bonilla, L.; Lopez-Machado, A. L.; Galindo, R.; Cano, A.; Espina, M.; Ettcheto, M.; Camins, A.; Silva, A. M.; Durazzo, A.; Santini, A.; Garcia, M. L.; Souto, E. B. Metal-Based Nanoparticles as Antimicrobial Agents: An Overview. Nanomaterials 2020, 10 (2), 292, DOI: 10.3390/nano10020292Google Scholar18Metal-based nanoparticles as antimicrobial agents: an overviewSanchez-Lopez, Elena; Gomes, Daniela; Esteruelas, Gerard; Bonilla, Lorena; Lopez-Machado, Ana Laura; Galindo, Ruth; Cano, Amanda; Espina, Marta; Ettcheto, Miren; Camins, Antoni; Silva, Amelia M.; Durazzo, Alessandra; Santini, Antonello; Garcia, Maria L.; Souto, Eliana B.Nanomaterials (2020), 10 (2), 292CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addn. to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-pos. and Gram-neg. bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their prodn. methods, physicochem. characterization, and pharmacokinetics together with the toxicol. risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-neg. bacteria has been highlighted.
- 19Broglie, J. J.; Alston, B.; Yang, C.; Ma, L.; Adcock, A. F.; Chen, W.; Yang, L. Antiviral Activity of Gold/Copper Sulfide Core/Shell Nanoparticles against Human Norovirus Virus-Like Particles. PLoS One 2015, 10 (10), e0141050 DOI: 10.1371/journal.pone.0141050Google Scholar19Antiviral activity of gold/copper sulfide core/shell nanoparticles against human norovirus virus-like particlesBroglie, Jessica Jenkins; Alston, Brittny; Yang, Chang; Ma, Lun; Adcock, Audrey F.; Chen, Wei; Yang, LijuPLoS One (2015), 10 (10), e0141050/1-e0141050/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Human norovirus is a leading cause of acute gastroenteritis worldwide in a plethora of residential and com. settings, including restaurants, schools, and hospitals. Methods for easily detecting the virus and for treating and preventing infection are crit. to stopping norovirus outbreaks, and inactivation via nanoparticles (NPs) is a more universal and attractive alternative to other phys. and chem. approaches. Using norovirus GI.1 (Norwalk) virus-like particles (VLPs) as a model viral system, this study characterized the antiviral activity of Au/CuS core/shell nanoparticles (NPs) against GI.1 VLPs for the rapid inactivation of HuNoV. Inactivation of VLPs (GI.1) by Au/CuS NPs evaluated using an absorbancebased ELISA indicated that treatment with 0.083 μM NPs for 10 min inactivated ∼50% VLPs in a 0.37 μg/mL VLP soln. and 0.83 μM NPs for 10 min completely inactivated the VLPs. Increasing nanoparticle concn. and/or VLP-NP contact time significantly increased the virucidal efficacy of Au/CuS NPs. Changes to the VLP particle morphol., size, and capsid protein were characterized using dynamic light scattering, transmission electron microscopy, and Western blot anal. The strategy reported here provides the first reported proof-of-concept Au/CuS NPs-based virucide for rapidly inactivating human norovirus.
- 20Kornblatt, A. P.; Nicoletti, V. G.; Travaglia, A. The Neglected Role of Copper Ions in Wound Healing. J. Inorg. Biochem. 2016, 161, 1– 8, DOI: 10.1016/j.jinorgbio.2016.02.012Google Scholar20The neglected role of copper ions in wound healingKornblatt, Allison Paige; Nicoletti, Vincenzo Giuseppe; Travaglia, AlessioJournal of Inorganic Biochemistry (2016), 161 (), 1-8CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)A review. Wound healing is a complex biol. process that aims to repair damaged tissue. Even though many biol. and biochem. mechanisms assocd. with the steps of physiol. wound healing are known, there is still significant morbidity and mortality due to dysregulation of physiol. mechanisms. It might be useful to revise the activity of old players and their links with new, often neglected, mol. entities. This review revises new findings supporting the hypothesis that copper ions regulate the activity and/or the expression of proteins crucially involved in the wound repair process. A better understanding of these interactions might suggest potential new targets for therapeutic intervention on scars or non-healing wounds.
- 21Yamada, M.; Foote, M.; Prow, T. W. Therapeutic Gold, Silver, and Platinum Nanoparticles. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2015, 7 (3), 428– 445, DOI: 10.1002/wnan.1322Google Scholar21Therapeutic gold, silver, and platinum nanoparticlesYamada, Miko; Foote, Matthew; Prow, Tarl W.Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology (2015), 7 (3), 428-445CODEN: WIRNBH; ISSN:1939-0041. (Wiley-Blackwell)A review. There are an abundance of nanoparticle technologies being developed for use as part of therapeutic strategies. This review focuses on a narrow class of metal nanoparticles that have therapeutic potential that is a consequence of elemental compn. and size. The most widely known of these are gold nanoshells that have been developed over the last two decades for photothermal ablation in superficial cancers. The therapeutic effect is the outcome of the thickness and diam. of the gold shell that enables fine tuning of the plasmon resonance. When these metal nanoparticles are exposed to the relevant wavelength of light, their temp. rapidly increases. This in turn induces a localized photothermal ablation that kills the surrounding tumor tissue. Similarly, gold nanoparticles have been developed to enhance radiotherapy. The high-Z nature of gold dramatically increases the photoelec. cross-section. Thus, the photoelec. effects are significantly increased. The outcome of these interactions is enhanced tumor killing with lower doses of radiation, all while sparing tissue without gold nanoparticles. Silver nanoparticles have been used for their wound healing properties in addn. to enhancing the tumor-killing effects of anticancer drugs. Finally, platinum nanoparticles are thought to serve as a reservoir for platinum ions that can induce DNA damage in cancer cells. The future is bright with the path to clin. trials is largely cleared for some of the less complex therapeutic metal nanoparticle systems.
- 22Rubilar, O.; Rai, M.; Tortella, G.; Diez, M. C.; Seabra, A. B.; Durán, N. Biogenic Nanoparticles: Copper, Copper Oxides, Copper Sulphides, Complex Copper Nanostructures and Their Applications. Biotechnol. Lett. 2013, 35 (9), 1365– 1375, DOI: 10.1007/s10529-013-1239-xGoogle Scholar22Biogenic nanoparticles: copper, copper oxides, copper sulphides, complex copper nanostructures and their applicationsRubilar, Olga; Rai, Mahendra; Tortella, Gonzalo; Diez, Maria Cristina; Seabra, Amedea B.; Duran, NelsonBiotechnology Letters (2013), 35 (9), 1365-1375CODEN: BILED3; ISSN:0141-5492. (Springer)A review. Copper nanoparticles have been the focus of intensive study due to their potential applications in diverse fields including biomedicine, electronics, and optics. Copper-based nanostructured materials have been used in conductive films, lubrification, nanofluids, catalysis, and also as potent antimicrobial agent. The biogenic synthesis of metallic nanostructured nanoparticles is considered to be a green and eco-friendly technol. since neither harmful chems. nor high temps. are involved in the process. The present review discusses the synthesis of copper nanostructured nanoparticles by bacteria, fungi, and plant exts., showing that biogenic synthesis is an economically feasible, simple and non-polluting process. Applications for biogenic copper nanoparticles are also discussed.
- 23Zhou, Y.; Wei, F.; Zhang, W.; Guo, Z.; Zhang, L. Copper Bioaccumulation and Biokinetic Modeling in Marine Herbivorous Fish Siganus Oramin. Aquat. Toxicol. 2018, 196, 61– 69, DOI: 10.1016/j.aquatox.2018.01.009Google Scholar23Copper bioaccumulation and biokinetic modeling in marine herbivorous fish Siganus oraminZhou, Yanyan; Wei, Fangsan; Zhang, Wei; Guo, Zhiqiang; Zhang, LiAquatic Toxicology (2018), 196 (), 61-69CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)Marine herbivorous fish directly consume macroalgae, which commonly accumulate high levels of trace metals in polluted areas. We proposed that herbivorous fish could be better candidates for biomonitoring marine metal pollution than carnivorous fish. To date, the trophic transfer of Cu from macroalgae to marine herbivorous fish is unclear. In this study, the kinetics of Cu bioaccumulation in a widespread marine herbivorous fish, Siganus oramin, were investigated, and biokinetic modeling was applied to est. the Cu levels in the fish sampled from different sites and seasons. The results showed that Cu accumulation in the fish was linearly correlated to the dietary Cu levels in the different prey species, which were proportional to the waterborne Cu concns. The Cu found in the subcellular trophically available metal fraction (TAM) in the prey contributed the largest proportion of accumulated Cu in S. oramin. The dietary assimilation efficiencies (AEs) of Cu were 15.56 ± 1.76%, 13.42 ± 2.86%, and 21.36 ± 1.47% for Ulva lactuca, Gracilaria lemaneiformis and Gracilaria gigas, resp. The calcd. waterborne uptake rate const. (ku) of Cu was 0.023 ± 0.011 L g-1 d-1, and the efflux rate const. (ke) was 0.055 ± 0.021 d-1. Dietary Cu accounted for 60%-75% of the body Cu in S. oramin, suggesting that dietary uptake could be the primary route for Cu bioaccumulation in herbivorous fish. The biokinetic model demonstrated that the Cu concns. in the water and fish presented a pos. linear relationship, which was in line with our field investigation along the coastal areas of South China. Therefore, we suggested that S. oramin could be used as a biomonitoring organism for Cu pollution in the marine environment. However, the heterogeneities between the predicted levels and the measured levels of Cu implied that seasonal changes should be taken into account to improve the accuracy of the model.
- 24Liu, Y.; Gao, Y.; Zhang, L.; Wang, T.; Wang, J.; Jiao, F.; Li, W.; Liu, Y.; Li, Y.; Li, B.; Chai, Z.; Wu, G.; Chen, C. Potential Health Impact on Mice after Nasal Instillation of Nano-Sized Copper Particles and Their Translocation in Mice. J. Nanosci. Nanotechnol. 2009, 9 (11), 6335– 6343, DOI: 10.1166/jnn.2009.1320Google Scholar24Potential health impact on mice after nasal instillation of nano-sized copper particles and their translocation in miceLiu, Yang; Gao, Yuxi; Zhang, Lili; Wang, Tiancheng; Wang, Jiangxue; Jiao, Fang; Li, Wei; Liu, Ying; Li, Yufeng; Li, Bai; Chai, Zhifang; Wu, Gang; Chen, ChunyingJournal of Nanoscience and Nanotechnology (2009), 9 (11), 6335-6343CODEN: JNNOAR; ISSN:1533-4880. (American Scientific Publishers)The purpose of this study is to evaluate the overall toxicity of nasal instilled nanoscale copper particles (23.5 nm) in mice. Pathol. examn., target organs identification, and blood biochem. assay of exptl. mice were carried out in comparison with micro-sized copper particles (17 μm). However, only in the high-dose group of copper nanoparticles (40 mg/kg body wt. instilled for three times in one week), the body wt. of mice were retarded and significant pathol. changes were obsd. There were hydropic degeneration around the central vein and the spotty necrosis of hepatocytes in the liver and swelling in the renal glomerulus, while, severe lesion assocd. with the decreased no. of olfactory cells and the dilapidated laminated structure were also obsd. in the olfactory bulb. The serum biochem. assay also indicated the sign of renal and hepatic lesion. However, there were no obvious pathol. and physiol. damages in the mice after instilling different-sized copper nanoparticles with low dose of 1 mg/kg body wt. The retention and distribution of copper in various tissues show that the liver, kidneys and olfactory bulb are the main accumulated tissues for copper particles, which were detd. by high sensitive element-specific technique of ICP-MS. The copper contents of the liver, kidneys and the olfactory bulb increase significantly at the group of 40 mg/kg compared to the control group, which is in agreement with the histol. changes. Therefore, the data indicate that nasal inhaled copper particles at very high dosage can translocate to other organs and tissues and further induce certain lesions. The present results are helpful to get better understanding of the risk assessment and evaluation for copper nanoparticles.
- 25Patel, R.; Aschner, M. Commonalities between Copper Neurotoxicity and Alzheimer’s Disease. Toxics 2021, 9 (1), 4, DOI: 10.3390/toxics9010004Google ScholarThere is no corresponding record for this reference.
- 26Karlsson, H. L.; Cronholm, P.; Gustafsson, J.; Möller, L. Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon Nanotubes. Chem. Res. Toxicol. 2008, 21 (9), 1726– 1732, DOI: 10.1021/tx800064jGoogle Scholar26Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon NanotubesKarlsson, Hanna L.; Cronholm, Pontus; Gustafsson, Johanna; Moeller, LennartChemical Research in Toxicology (2008), 21 (9), 1726-1732CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Since the manuf. and use of nanoparticles are increasing, humans are more likely to be exposed occupationally or via consumer products and the environment. However, so far toxicity data for most manufd. nanoparticles are limited. The aim of this study was to investigate and compare different nanoparticles and nanotubes regarding cytotoxicity and ability to cause DNA damage and oxidative stress. The study was focused on different metal oxide particles (CuO, TiO2, ZnO, CuZnFe2O4, Fe3O4, Fe2O3), and the toxicity was compared to that of carbon nanoparticles and multiwalled carbon nanotubes (MWCNT). The human lung epithelial cell line A549 was exposed to the particles, and cytotoxicity was analyzed using trypan blue staining. DNA damage and oxidative lesions were detd. using the comet assay, and intracellular prodn. of reactive oxygen species (ROS) was measured using the oxidn.-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate (DCFH-DA). The results showed that there was a high variation among different nanoparticles concerning their ability to cause toxic effects. CuO nanoparticles were most potent regarding cytotoxicity and DNA damage. The toxicity was likely not explained by Cu ions released to the cell medium. These particles also caused oxidative lesions and were the only particles that induced an almost significant increase (p = 0.058) in intracellular ROS. ZnO showed effects on cell viability as well as DNA damage, whereas the TiO2 particles (a mix of rutile and anatase) only caused DNA damage. For iron oxide particles (Fe3O4, Fe2O3), no or low toxicity was obsd., but CuZnFe2O4 particles were rather potent in inducing DNA lesions. Finally, the carbon nanotubes showed cytotoxic effects and caused DNA damage in the lowest dose tested. The effects were not explained by sol. metal impurities. In conclusion, this study highlights the in vitro toxicity of CuO nanoparticles.
- 27Bahadar, H.; Maqbool, F.; Niaz, K.; Abdollahi, M. Toxicity of Nanoparticles and an Overview of Current Experimental Models. Iranian Biomedical Journal 2016, 20 (1), 1– 11, DOI: 10.7508/ibj.2016.01.001Google Scholar28Toxicity of Nanoparticles and an Overview of Current Experimental ModelsBahadar Haji; Maqbool Faheem; Niaz Kamal; Abdollahi Mohammad; Abdollahi Mohammad; Abdollahi MohammadIranian biomedical journal (2016), 20 (1), 1-11 ISSN:.Nanotechnology is a rapidly growing field having potential applications in many areas. Nanoparticles (NPs) have been studied for cell toxicity, immunotoxicity, and genotoxicity. Tetrazolium-based assays such as MTT, MTS, and WST-1 are used to determine cell viability. Cell inflammatory response induced by NPs is checked by measuring inflammatory biomarkers, such as IL-8, IL-6, and tumor necrosis factor, using ELISA. Lactate dehydrogenase (LDH) assay is used for cell membrane integrity. Different types of cell cultures, including cancer cell lines have been employed as in vitro toxicity models. It has been generally agreed that NPs interfere with either assay materials or with detection systems. So far, toxicity data generated by employing such models are conflicting and inconsistent. Therefore, on the basis of available experimental models, it may be difficult to judge and list some of the more valuable NPs as more toxic to biological systems and vice versa. Considering the potential applications of NPs in many fields and the growing apprehensions of FDA about the toxic potential of nanoproducts, it is the need of the hour to look for new internationally agreed free of bias toxicological models by focusing more on in vivo studies.
- 28Studer, A. M.; Limbach, L. K.; Van Duc, L.; Krumeich, F.; Athanassiou, E. K.; Gerber, L. C.; Moch, H.; Stark, W. J. Nanoparticle Cytotoxicity Depends on Intracellular Solubility: Comparison of Stabilized Copper Metal and Degradable Copper Oxide Nanoparticles. Toxicol. Lett. 2010, 197 (3), 169– 174, DOI: 10.1016/j.toxlet.2010.05.012Google Scholar29Nanoparticle cytotoxicity depends on intracellular solubility: Comparison of stabilized copper metal and degradable copper oxide nanoparticlesStuder, Andreas M.; Limbach, Ludwig K.; Duc, Luu Van; Krumeich, Frank; Athanassiou, Evagelos K.; Gerber, Lukas C.; Moch, Holger; Stark, Wendelin J.Toxicology Letters (2010), 197 (3), 169-174CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Metal nanoparticles have distinctly different chem. and phys. properties than currently investigated oxides. Since pure metallic nanoparticles are igniting at air, carbon stabilized copper nanoparticles were used as representative material for this class. Using copper as a representative example, we compare the cytotoxicity of copper metal nanoparticles stabilized by a carbon layer to copper oxide nanoparticles using two different cell lines. Keeping the copper exposure dose const., the two forms of copper showed a distinctly different response. While copper oxide had already been reported to be highly cytotoxic, carbon-coated copper nanoparticles were much less cytotoxic and more tolerated. Measuring the two material's intra- and extracellular soly. in model buffers explained this difference on the basis of altered copper release when supplying copper metal or the corresponding oxide particles to the cells. Control expts. using pure carbon nanoparticles were used to exclude significant surface effects. Ref. expts. with ionic copper solns. confirmed a similar response of cultures if exposed to copper oxide nanoparticles or ionic copper. These observations are in line with a Trojan horse-type mechanism and illustrate the dominating influence of physico-chem. parameters on the cytotoxicity of a given metal.
- 29Applerot, G.; Lellouche, J.; Lipovsky, A.; Nitzan, Y.; Lubart, R.; Gedanken, A.; Banin, E. Understanding the Antibacterial Mechanism of CuO Nanoparticles: Revealing the Route of Induced Oxidative Stress. Small 2012, 8 (21), 3326– 3337, DOI: 10.1002/smll.201200772Google Scholar30Understanding the antibacterial mechanism of CuO nanoparticles: revealing the route of induced oxidative stressApplerot, Guy; Lellouche, Jonathan; Lipovsky, Anat; Nitzan, Yeshayahu; Lubart, Rachel; Gedanken, Aharon; Banin, EhudSmall (2012), 8 (21), 3326-3337CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)To date, there is still a lack of definite knowledge regarding the interaction of CuO nanoparticles with bacteria and the possible permeation of the nanoparticles into bacterial cells. This study was aimed at shedding light on the size-dependent (from the microscale down to the small nanoscale) antibacterial activity of CuO. The potent antibacterial activity of CuO nanoparticles was found to be due to ROS generation by the nanoparticles attached to the bacterial cells, which in turn provoked an enhancement of the intracellular oxidative stress. This paradigm was confirmed by several assays such as lipid peroxidn. and reporter strains of oxidative stress. Furthermore, electron microscopy indicated that the small nanoparticles of CuO penetrated the cells. Thus, the results reported herein may reconcile conflicting concepts in the literature concerning the antibacterial mechanism of CuO nanoparticles, as well as highlight the potential for developing sustainable CuO nanoparticles-based devices for inhibiting bacterial infections.
- 30Karlsson, H. L.; Cronholm, P.; Hedberg, Y.; Tornberg, M.; De Battice, L.; Svedhem, S.; Wallinder, I. O. Cell Membrane Damage and Protein Interaction Induced by Copper Containing Nanoparticles-Importance of the Metal Release Process. Toxicology 2013, 313 (1), 59– 69, DOI: 10.1016/j.tox.2013.07.012Google Scholar31Cell membrane damage and protein interaction induced by copper containing nanoparticles-Importance of the metal release processKarlsson, Hanna L.; Cronholm, Pontus; Hedberg, Yolanda; Tornberg, Malin; De Battice, Laura; Svedhem, Sofia; Wallinder, Inger OdnevallToxicology (2013), 313 (1), 59-69CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)Cu-contg. nanoparticles are used in various applications in order to e.g. achieve antimicrobial activities and to increase the cond. of fluids and polymers. Several studies have reported on toxic effects of such particles but the mechanisms are not completely clear. The aim of this study was to investigate the interactions between cell membranes and well-characterized nanoparticles of CuO, Cu metal, a binary Cu-Zn alloy and micron-sized Cu metal particles. This was conducted via in vitro investigations of the effects of the nanoparticles on (i) cell membrane damage on lung epithelial cells (A549), (ii) membrane rupture of red blood cells (hemolysis), complemented by (iii) nanoparticle interaction studies with a model lipid membrane using quartz crystal microbalance with dissipation monitoring (QCM-D). The results revealed that nanoparticles of the Cu metal and the Cu-Zn alloy were both highly membrane damaging and caused a rapid (within 1 h) increase in membrane damage at a particle mass dose of 20 μg/mL, whereas the CuO nanoparticles and the micron-sized Cu metal particles showed no such effect. At similar nanoparticle surface area doses, the nano and micron-sized Cu particles showed more similar effects. The commonly used LDH (lactate dehydrogenase) assay for anal. of membrane damage was found impossible to use due to nanoparticle-assay interactions. None of the particles induced any hemolytic effects on red blood cells when investigated up to high particle concns. (1 mg/mL). However, both Cu and Cu-Zn nanoparticles caused Hb aggregation/pptn., a process that would conceal a possible hemolytic effect. Studies on interactions between the nanoparticles and a model membrane using QCM-D indicated a small difference between the investigated particles. Results of this study suggest that the obsd. membrane damage is caused by the metal release process at the cell membrane surface and highlight differences in reactivity between metallic nanoparticles of Cu and Cu-Zn and nanoparticles of CuO.
- 31Wang, Z.; Li, N.; Zhao, J.; White, J. C.; Qu, P.; Xing, B. CuO Nanoparticle Interaction with Human Epithelial Cells: Cellular Uptake, Location, Export, and Genotoxicity. Chem. Res. Toxicol. 2012, 25 (7), 1512– 1521, DOI: 10.1021/tx3002093Google Scholar32CuO Nanoparticle Interaction with Human Epithelial Cells: Cellular Uptake, Location, Export, and GenotoxicityWang, Zhenyu; Li, Na; Zhao, Jian; White, Jason C.; Qu, Pei; Xing, BaoshanChemical Research in Toxicology (2012), 25 (7), 1512-1521CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The toxicity of CuO nanoparticles (NPs) to human lung epithelial (A549) cells was investigated in this study. CuO NPs (10-100 mg/L) had significant toxicity to A549 cells, whereas CuO bulk particles (BPs) showed much lower toxicity (24 h IC50, 58 and 15 mg/L for CuO BPs and NPs, resp.). Transmission electron microscopic anal. demonstrated CuO NP entry into A549 cells and organelles, including lysosomes, mitochondria, and nucleus. Endocytosis was the primary pathway of CuO NPs uptake. CuO NPs (15 mg/L) induced mitochondrial depolarization, possibly mediated by reactive oxygen species (ROS) generation. Intracellular CuO NPs 1st generate ROS, which subsequently induces the expression of p38 and p53 and ultimately causes DNA damage (Comet assay). We confirm for the 1st time that the primary cytotoxic response is oxidative stress rather than DNA damage. A fraction of the CuO NPs was exported to the extracellular environment. In this study, centrifugal ultrafiltration tubes were successfully employed to det. the dissolved Cu2+ from CuO NPs in the cell medium. Dissolved Cu2+ ions contributed less than half of the total toxicity caused by CuO NPs, including ROS generation and DNA damage. This study provided useful data for understanding transport and toxicity of metal oxide NPs in human cells.
- 32Vanwinkle, B. A.; De Mesy Bentley, K. L.; Malecki, J. M.; Gunter, K. K.; Evans, I. M.; Elder, A.; Finkelstein, J. N.; Oberdörster, G.; Gunter, T. E. Nanoparticle (NP) Uptake by Type i Alveolar Epithelial Cells and Their Oxidant Stress Response. Nanotoxicology 2009, 3 (4), 307– 318, DOI: 10.3109/17435390903121949Google Scholar33Nanoparticle (NP) uptake by type I alveolar epithelial cells and their oxidant stress responseVanwinkle, Beth A.; de Mesy Bentley, Karen L.; Malecki, Jonathan M.; Gunter, Karlene K.; Evans, Irene M.; Elder, Alison; Finkelstein, Jacob N.; Oberdorster, Gunter; Gunter, Thomas E.Nanotoxicology (2009), 3 (4), 307-318CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)Mammalian cells take up nanoparticles (NPs) and some NPs increase ROS. We used imaging and measure ROS in parallel to evaluate NP-cell interactions with type I-like alveolar epithelial cells exposed to NPs at 1.2 μg/cm2. Titanium dioxide (TiO2), gold (Au), silver (Ag), and manganese (Mn) were internalized by R3-1 cells; copper (Cu) NPs were obsd. at the cell surface only. TiO2 and Au did not increase cell death but Mn and Cu did, with surviving cells recovering after initial Cu exposure. Ag NPs caused 80% of R3-1 cells to lift off the slides within 1 h. Amplex Red was used to report H2O2 prodn. after exposure to 0.4 μg/cm2 TiO2, Au, Cu, Mn and Ag. TiO2, Au, and Ag caused no significant increase in H2O2 while Cu and Mn increased H2O2. NPs that give up electrons, increase ROS prodn. and cause cell death in R3-1 cells.
- 33Cronholm, P.; Midander, K.; Karlsson, H. L.; Elihn, K.; Wallinder, I. O.; Möller, L. Effect of Sonication and Serum Proteins on Copper Release from Copper Nanoparticles and the Toxicity towards Lung Epithelial Cells. Nanotoxicology 2011, 5 (2), 269– 281, DOI: 10.3109/17435390.2010.536268Google Scholar34Effect of sonication and serum proteins on copper release from copper nanoparticles and the toxicity towards lung epithelial cellsCronholm, Pontus; Midander, Klara; Karlsson, Hanna L.; Elihn, Karine; Wallinder, Inger Odnevall; Moeller, LennartNanotoxicology (2011), 5 (2), 269-281CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)Different methodol. settings can influence particle characteristics and toxicity in nanotoxicol. The aim of this study was to investigate how serum proteins and sonication of Cu nanoparticle suspensions influence the properties of the nanoparticles and toxicol. responses on human lung epithelial cells. This was investigated by using methods for particle characterization (photon correlation spectroscopy and TEM) and Cu release (at. absorption spectroscopy) in combination with assays for analyzing cell toxicity (MTT-, trypan blue- and Comet assay). The results showed that sonication of Cu nanoparticles caused decreased cell viability and increased Cu release compared to non-sonicated particles. Furthermore, serum in the cell medium resulted in less particle agglomeration and increased Cu release compared with medium without serum, but no clear difference in toxicity was detected. Few cells showed intracellular Cu nanoparticles due to fast release/dissoln. processes of Cu. In conclusion; sonication can affect the toxicity of nanoparticles.
- 34Laha, D.; Pramanik, A.; Laskar, A.; Jana, M.; Pramanik, P.; Karmakar, P. Shape-Dependent Bactericidal Activity of Copper Oxide Nanoparticle Mediated by DNA and Membrane Damage. Mater. Res. Bull. 2014, 59, 185– 191, DOI: 10.1016/j.materresbull.2014.06.024Google Scholar35Shape-dependent bactericidal activity of copper oxide nanoparticle mediated by DNA and membrane damageLaha, Dipranjan; Pramanik, Arindam; Laskar, Aparna; Jana, Madhurya; Pramanik, Panchanan; Karmakar, ParimalMaterials Research Bulletin (2014), 59 (), 185-191CODEN: MRBUAC; ISSN:0025-5408. (Elsevier Ltd.)In this work, we synthesized spherical and sheet shaped copper oxide nanoparticles and their phys. characterizations were done by the X-ray diffraction, fourier transform IR spectroscopy, transmission electron microscopy and dynamic light scattering. The antibacterial activity of these nanoparticles was detd. on both gram pos. and gram neg. bacterial. Spherical shaped copper oxide nanoparticles showed more antibacterial property on gram pos. bacteria where as sheet shaped copper oxide nanoparticles are more active on gram neg. bacteria. We also demonstrated that copper oxide nanoparticles produced reactive oxygen species in both gram neg. and gram pos. bacteria. Furthermore, they induced membrane damage as detd. by at. force microscopy and SEM. Thus prodn. of and membrane damage are major mechanisms of the bactericidal activity of these copper oxide nanoparticles. Finally it was concluded that antibacterial activity of nanoparticles depend on physicochem. properties of copper oxide nanoparticles and bacterial strain.
- 35Betancourt-Galindo, R.; Reyes-Rodriguez, P. Y.; Puente-Urbina, B. A.; Avila-Orta, C. A.; Rodríguez-Fernández, O. S.; Cadenas-Pliego, G.; Lira-Saldivar, R. H.; García-Cerda, L. A. Synthesis of Copper Nanoparticles by Thermal Decomposition and Their Antimicrobial Properties. J. Nanomater. 2014, 980545, DOI: 10.1155/2014/980545Google Scholar36Synthesis of copper nanoparticles by thermal decomposition and their antimicrobial propertiesBetancourt-Galindo, R.; Reyes-Rodriguez, P. Y.; Puente-Urbina, B. A.; Avila-Orta, C. A.; Rodriguez-Fernandez, O. S.; Cadenas-Pliego, G.; Lira-Saldivar, R. H.; Garcia-Cerda, L. A.Journal of Nanomaterials (2014), (), 980545/1-980545/6, 6CODEN: JNOABP; ISSN:1687-4129. (Hindawi Publishing Corp.)Copper nanoparticles were synthesized by thermal decompn. using copper chloride, sodium oleate, and Ph ether as solvent agents.The formation of nanoparticles was evidenced by the X-ray diffraction and transmission electron microscopy. The peaks in the XRD pattern correspond to the std. values of the fcc. (fcc) structure of metallic copper and no peaks of other impurity cryst. phases were detected. TEM anal. showed spherical nanoparticles with sizes in the range of 4 to 18 nm. The antibacterial properties of copper nanoparticles were evaluated in vitro against strains of Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial activity of copper nanoparticles synthesized by thermal decompn. showed significant inhibitory effect against these highly multidrug-resistant bacterial strains.
- 36Zhou, J.; Xiang, H.; Zabihi, F.; Yu, S.; Sun, B.; Zhu, M. Intriguing Anti-Superbug Cu2O@ZrP Hybrid Nanosheet with Enhanced Antibacterial Performance and Weak Cytotoxicity. Nano Res. 2019, 12 (6), 1453– 1460, DOI: 10.1007/s12274-019-2406-8Google Scholar37Intriguing anti-superbug Cu2O@ZrP hybrid nanosheet with enhanced antibacterial performance and weak cytotoxicityZhou, Jialiang; Xiang, Hengxue; Zabihi, Fatemeh; Yu, Senlong; Sun, Bin; Zhu, MeifangNano Research (2019), 12 (6), 1453-1460CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)In view of it's strong antibacterial function and minor toxicity, cuprous oxide (Cu2O) is frequently used in various broad-spectrum antibacterial reagents. Nonetheless the undesirable effects of superbugs still remain challenging. In this research, a chem. deposition approach is used to prep. a Cu2O@ZrP composite with nanosheet configuration demonstrating excellent dispersibility and antibacterial traits. From systematic anal., it was inffered that the content of copper in the nanosheet was about 57-188 mg/g while the av. thickness of the nanosheets Cu2O formed on ZrP is approx. 0.8 nm. The results of the minimal inhibitory concn. (MIC) revealed that an extremely low loading of Cu2O in Cu2O@ZrP nanosheet can lead to exceptional antibacterial activity. Examd. on two various superbugs; i.e. methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE), the composite nanosheet reagent performed over 99% microbial redn. More intesetingly, the cell growth rate of the Cu2O@ZrP nanosheet was detd. to be 20% lower than that of the neat Cu2O, manifesting a weaker cytotoxicity. This unique hybrid nanosheet with intriguing anti-superbug performance promises highly efficient protection for the fabrics, battledress, and medical textiles.
- 37Shalom, Y.; Perelshtein, I.; Perkas, N.; Gedanken, A.; Banin, E. Catheters Coated with Zn-Doped CuO Nanoparticles Delay the Onset of Catheter-Associated Urinary Tract Infections. Nano Res. 2017, 10 (2), 520– 533, DOI: 10.1007/s12274-016-1310-8Google Scholar38Catheters coated with Zn-doped CuO nanoparticles delay the onset of catheter-associated urinary tract infectionsShalom, Yakov; Perelshtein, Ilana; Perkas, Nina; Gedanken, Aharon; Banin, EhudNano Research (2017), 10 (2), 520-533CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)Catheter-assocd. urinary tract infections (CAUTIs) are among the most common bacterial infections assocd. with medical devices. In the current study, the synthesis, coating, antibiofilm properties, and biocompatibility of urinary catheters coated with Zn-doped CuO (Zn0.12Cu0.88O) nanoparticles (NPs) were examd. The doped NPs were synthesized and subsequently deposited on the catheter by the sonochem. method. The coated catheters displayed high antibiofilm activity and promising biocompatibility, as indicated by low in vitro cytotoxicity, negligible assocd. cytokine secretion, and absence of detectable irritation. The biocompatibility and ability of the Zn-doped CuO coating to inhibit biofilm formation were also evaluated in vivo using a rabbit model. Rabbits catheterized with uncoated catheters scored pos. for CAUTI by day 4 of the expt. In contrast, rabbits catheterized with Zn-doped CuO-coated catheters did not exhibit CAUTI until day 7 or remained completely uninfected for the whole duration of the 7-day expt. Furthermore, the in vivo biocompatibility assays and examns. supported the biosafety of Zn-doped CuO-coated catheters. Taken together, these data highlight the potential of Zn-doped CuO nanocomposite as effective antibiofilm compd.[Figure not available: see fulltext.].
- 38El-Batal, A. I.; Al-Hazmi, N. E.; Mosallam, F. M.; El-Sayyad, G. S. Biogenic Synthesis of Copper Nanoparticles by Natural Polysaccharides and Pleurotus Ostreatus Fermented Fenugreek Using Gamma Rays with Antioxidant and Antimicrobial Potential towards Some Wound Pathogens. Microb. Pathog. 2018, 118, 159– 169, DOI: 10.1016/j.micpath.2018.03.013Google Scholar39Biogenic synthesis of copper nanoparticles by natural polysaccharides and Pleurotus ostreatus fermented fenugreek using gamma rays with antioxidant and antimicrobial potential towards some wound pathogensEl-Batal, Ahmed I.; Al-Hazmi, Nawal E.; Mosallam, Farag M.; El-Sayyad, Gharieb S.Microbial Pathogenesis (2018), 118 (), 159-169CODEN: MIPAEV; ISSN:0882-4010. (Elsevier Ltd.)Mono-dispersed copper nanoparticles (CuNPs) were constructed using cheap polysaccharides (citrus pectin, chitosan, and sodium alginate), and by appropriating aq. fermented fenugreek powder (FFP) under the action of Pleurotus ostreatus (as reducing and preserving means), through the influence of gamma irradn. The synthesized CuNPs are described by UV-Vis. spectroscopy TEM, DLS, XRD, and FT-IR. XRD study of the CuNPs confirmed the generation of metallic CuNPs. The nucleation and the prodn. mechanism of CuNPs are moreover explained. TEM unveiled that, the ordinary diam. of CuNPs incorporated by various polysaccharides, and FFP taken in the range of 31.0 and 36.0 nm resp. CuNPs size is influenced by many parameters such as the variety of stabilizer, pH within the organization and applied gamma dose. Evaluation of the antioxidant and antimicrobial activities of CuNPs was performed against some selected wound pathogens. The results showed that, CuNPs were a strong antimicrobial agents against microbes caused burn skin infection such as Klebsiella pneumoniae, Staphylococcus aureus, and Candida albicans (16.0, 15.0, and 15.0 mm ZOI, resp.). Addnl., CuNPs have a strong antioxidant with 70% scavenging activity against DPPH. So, due to unique characteristics of CuNPs (cost-effective with continued-term stabilization and effective features), they can recover reasonable potential in biomedical, industrial, agricultural, cosmetics, dermal products and pharmaceutical purposes.
- 39Rubilar, O.; Rai, M.; Tortella, G.; Diez, M. C.; Seabra, A. B.; Durán, N. Biogenic Nanoparticles: Copper, Copper Oxides, Copper Sulphides, Complex Copper Nanostructures and Their Applications. Biotechnol. Lett. 2013, 35, 1365– 1375, DOI: 10.1007/s10529-013-1239-xGoogle Scholar40Biogenic nanoparticles: copper, copper oxides, copper sulphides, complex copper nanostructures and their applicationsRubilar, Olga; Rai, Mahendra; Tortella, Gonzalo; Diez, Maria Cristina; Seabra, Amedea B.; Duran, NelsonBiotechnology Letters (2013), 35 (9), 1365-1375CODEN: BILED3; ISSN:0141-5492. (Springer)A review. Copper nanoparticles have been the focus of intensive study due to their potential applications in diverse fields including biomedicine, electronics, and optics. Copper-based nanostructured materials have been used in conductive films, lubrification, nanofluids, catalysis, and also as potent antimicrobial agent. The biogenic synthesis of metallic nanostructured nanoparticles is considered to be a green and eco-friendly technol. since neither harmful chems. nor high temps. are involved in the process. The present review discusses the synthesis of copper nanostructured nanoparticles by bacteria, fungi, and plant exts., showing that biogenic synthesis is an economically feasible, simple and non-polluting process. Applications for biogenic copper nanoparticles are also discussed.
- 40Shobha, G.; Moses, V.; Ananda, S. Biological Synthesis of Copper Nanoparticles and Its Impact - A Review. Int. J. Pharm. Sci. Invent. 2014, 3 (8), 28– 38Google ScholarThere is no corresponding record for this reference.
- 41Rafique, M.; Shaikh, A. J.; Rasheed, R.; Tahir, M. B.; Bakhat, H. F.; Rafique, M. S.; Rabbani, F. A Review on Synthesis, Characterization and Applications of Copper Nanoparticles Using Green Method. Nano 2017, 12 (4), 1750043, DOI: 10.1142/S1793292017500436Google Scholar42A Review on Synthesis, Characterization and Applications of Copper Nanoparticles Using Green MethodRafique, Muhammad; Shaikh, Ahson J.; Rasheed, Reena; Tahir, Muhammad Bilal; Bakhat, Hafiz Faiq; Rafique, Muhammad Shahid; Rabbani, FaizNano (2017), 12 (4), 1750043CODEN: NANOFJ; ISSN:1793-2920. (World Scientific Publishing Co. Pte. Ltd.)To address accosts of this modern age, the synthesis of metal nanoparticles is more important than ever. Copper has been recognized as a nontoxic, safe inorg. material, cheaper antibacterial/antifungal agent, and has high potential in a wide range of biol., catalytic and sensors applications more particularly in the form of nanoparticles. This resulted in the development of numerous methods for the synthesis of copper nanoparticles. As conventional methods like chem. and phys. methods have several limitations so there is need to an alternate method. Due to nontoxic and eco-friendly nature, it has recently been shifted toward green synthesis of copper nanoparticles over conventional methods. Addnl., characterization of the synthesized nanoparticles is essential for their use in various applications. This review gives an overview of environment friendly synthesis method of copper nanoparticles and their applications on the basis of their potential selectivity and preferences in a no. of fields like material sciences and biomedicine.
- 42Delgado, K.; Quijada, R.; Palma, R.; Palza, H. Polypropylene with Embedded Copper Metal or Copper Oxide Nanoparticles as a Novel Plastic Antimicrobial Agent. Lett. Appl. Microbiol. 2011, 53, 50– 54, DOI: 10.1111/j.1472-765X.2011.03069.xGoogle Scholar4300Polypropylene with embedded copper metal or copper oxide nanoparticles as a novel plastic antimicrobial agentDelgado, K.; Quijada, R.; Palma, R.; Palza, H.Letters in Applied Microbiology (2011), 53 (1), 50-54CODEN: LAMIE7; ISSN:0266-8254. (Wiley-Blackwell)Aims: To develop novel polypropylene composite materials with antimicrobial activity by adding different types of copper nanoparticles. Methods and Results: Copper metal (CuP) and copper oxide nanoparticles (CuOP) were embedded in a polypropylene (PP) matrix. These composites present strong antimicrobial behavior against E. coli that depends on the contact time between the sample and the bacteria. After just 4 h of contact, these samples are able to kill more than 95% of the bacteria. CuOP fillers are much more effective eliminating bacteria than CuP fillers, showing that the antimicrobial property further depends on the type of copper particle. Cu2+ released from the bulk of the composite is responsible for this behavior. Moreover, PP/CuOP composites present a higher release rate than PP/CuP composites in a short time, explaining the antimicrobial tendency. Conclusions: Polypropylene composites based on copper nanoparticles can kill E. coli bacteria depending on the release rate of Cu2+ from the bulk of the material. CuOP are more effective as antimicrobial filler than CuP. Significance and Impact of the Study: Our findings open up novel applications of these ion-copper-delivery plastic materials based on PP with embedded copper nanoparticles with great potential as antimicrobial agents.
- 43Xiao, J.; Zhu, Y.; HUddleston, S.; Li, P.; Xiao, B.; Farha, O. K.; Ameer, G. A. Copper Metal−Organic Framework Nanoparticles Stabilized with Folic Acid Improve Wound Healing in Diabetes. ACS Nano 2018, 12, 1023– 1032, DOI: 10.1021/acsnano.7b01850Google Scholar4301Copper Metal-Organic Framework Nanoparticles Stabilized with Folic Acid Improve Wound Healing in DiabetesXiao, Jisheng; Zhu, Yunxiao; Huddleston, Samantha; Li, Peng; Xiao, Baixue; Farha, Omar K.; Ameer, Guillermo A.ACS Nano (2018), 12 (2), 1023-1032CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper-based metal-org. framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solns., can be modified to slowly release Cu2+, resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addn., cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu2+ release, thus enabling the direct application of Cu-MOF NPs to wounds.
- 44Rasool, U.; Hemalatha, S. Marine Endophytic Actinomycetes Assisted Synthesis of Copper Nanoparticles (CuNPs): Characterization and Antibacterial Efficacy against Human Pathogens. Mater. Lett. 2017, 194, 176– 180, DOI: 10.1016/j.matlet.2017.02.055Google Scholar43Marine endophytic actinomycetes assisted synthesis of copper nanoparticles (CuNPs): Characterization and antibacterial efficacy against human pathogensRasool, Ubaid; Hemalatha, S.Materials Letters (2017), 194 (), 176-180CODEN: MLETDJ; ISSN:0167-577X. (Elsevier B.V.)Marine endophytic actinomycetes isolated from seaweeds was used in assisting the synthesis of copper nanoparticles which were characterized by UV-Visible spectroscopy, FTIR, SEM, TEM, and assessed for antibacterial activity against 5 different human pathogenic bacteria. Freshly synthesized copper nanoparticles showed 2 absorption bands at 370 nm and 690 nm due to their variable size. FTIR anal. confirmed the capping and stabilization, SEM anal. depicted the morphol., EDX anal. confirmed the presence and TEM anal. provided the size and shape of synthesized copper nanoparticles. Antibacterial activity was obsd. through zones of inhibition. The results suggested that copper nanoparticles synthesized by the assistance of actinomycetes can be utilized to control the human pathogenic bacteria.
- 45Bocarando-Chacón, J.; Vargas-Vazquez, D.; Martinez-Suarez, F.; Flores-Juárez, C.; Cortez-Valadez, M. Surface-Enhanced Raman Scattering and Antibacterial Properties from Copper Nanoparticles Obtained by Green Chemistry. Appl. Phys. A: Mater. Sci. Process. 2020, 126 (7), 530, DOI: 10.1007/s00339-020-03704-1Google Scholar44Surface-enhanced Raman scattering and antibacterial properties from copper nanoparticles obtained by green chemistryBocarando-Chacon, J.; Vargas-Vazquez, D.; Martinez-Suarez, F.; Flores-Juarez, C.; Cortez-Valadez, M.Applied Physics A: Materials Science & Processing (2020), 126 (7), 530CODEN: APAMFC; ISSN:0947-8396. (Springer)In this study, copper nanoparticles (CuNPs) were synthesized using the ext. of Opuntia ficus-Indica and Geranium as a reducing agent. By transmission electron microscopy, the morphol. of the nanoparticles was detd. to be mostly spherical, with a particle size about 3-10 nm. The UV-Vis spectra displayed absorption bands between 525 and 550 nm, assocd. with the surface plasmon resonance in the CuNPs. The various particle sizes obtained were tested as SERS substrate with the pyridine mol. Antibacterial activity of copper nanoparticles against Escherichia coli gram-neg. bacteria was studied. Bacteriol. inhibition tests were performed on nutrient agar plates supplemented with different concns. of copper nanoparticles. The copper nanoparticles with a concn. of 150μg/mL and a size distribution around 6 nm showed the largest bactericidal effectiveness against E. coli.
- 46Amorim, A.; Mafud, A. C. pd; Nogueira, S.; Jesus, J. R.; Araújo, A. R.; de Plácido, A.; Brito Neta, M.; Alves, M. M. M.; Carvalho, F. A. A.; Rufino Arcanjo, D. D.; Braun, S.; López, M. S. P.; López-Ruiz, B.; Delerue-Matos, C.; Mascarenhas, Y.; Silva, D.; Eaton, P.; Almeida Leite, J. R. S. Copper Nanoparticles Stabilized with Cashew Gum: Antimicrobial Activity and Cytotoxicity against 4T1Mouse Mammary Tumor Cell Line. J. Biomater. Appl. 2019, 34 (2), 188– 197, DOI: 10.1177/0885328219845964Google Scholar45Copper nanoparticles stabilized with cashew gum: Antimicrobial activity and cytotoxicity against 4T1 mouse mammary tumor cell lineAmorim, Adriany; Mafud, Ana Carolina; Nogueira, Silvania; Jesus, Joilson Ramos; de Araujo, Alyne Rodrigues; Placido, Alexandra; Brito Neta, Maria; Alves, Michel Mualem Moraes; Carvalho, Fernando Aecio Amorim; Rufino Arcanjo, Daniel Dias; Braun, Sacha; Lopez, Marta Sanchez-Paniagua; Lopez-Ruiz, Beatriz; Delerue-Matos, Cristina; Mascarenhas, Yvonne; Silva, Durcilene; Eaton, Peter; Almeida Leite, Jose Roberto SouzaJournal of Biomaterials Applications (2019), 34 (2), 188-197CODEN: JBAPEL; ISSN:0885-3282. (Sage Publications Ltd.)Copper nanoparticles stabilized with cashew (CG-CuNPs) were synthesized by redn. reaction using ascorbic acid and sodium borohydride, using the cashew gum (CG) as a natural polymer stabilizer. Dynamic light scattering, at. force microscopy, Fourier-transform IR spectroscopy, UV-Vis spectrophotometry, and x-ray diffraction were used to characterize the nanoparticles (CG-CuNPs), and copper was quantified by electrochem. measurement. The UV-vis spectra of the CG-CuNPs confirmed the formation of nanoparticles by appearance of a surface plasmon band at 580 nm after 24 h of reaction. The Fourier-transform IR spectrum of CG-CuNPs showed the peak at 1704 cm-1 from cashew gum, confirming the presence of the gum in the nanoparticles. The av. size of CG-CuNPs by dynamic light scattering and at. force microscopy was around 10 nm, indicating small, approx. spherical particles. Antimicrobial assays showed that CG-CuNPs had activity against Staphylococcus aureus ATCC 29213 with a minimal inhibitory concn. of 0.64 mM. The cytotoxicity assay on BALB/c murine macrophages showed lower cytotoxic effects for CG-CuNPs than CuSO4·5H2O. Viability cell assays for CG-CuNPs at (0.250 mM) inhibited by 70% the growth of 4T1 LUC (4T1 mouse mammary tumor cell line) and NIH 3T3 cells (murine fibroblast cells) over a 24-h period. Therefore, CG-CuNPs can be used as an antimicrobial agent with lower cytotoxic effects than the CuSO4·5H2O precursor.
- 47Zhao, H.; Su, H.; Ahmeda, A.; Sun, Y.; Li, Z.; Zangeneh, M. M.; Nowrozi, M.; Zangeneh, A.; Moradi, R. Biosynthesis of Copper Nanoparticles Using Allium Eriophyllum Boiss Leaf Aqueous Extract; Characterization and Analysis of Their Antimicrobial and Cutaneous Wound-Healing Potentials. Appl. Organomet. Chem. 2020, DOI: 10.1002/aoc.5587Google ScholarThere is no corresponding record for this reference.
- 48Yaqub, A.; Malkani, N.; Shabbir, A.; Ditta, S. A.; Tanvir, F.; Ali, S.; Naz, M.; Kazmi, S. A. R.; Ullah, R. Novel Biosynthesis of Copper Nanoparticles Using Zingiber and Allium Sp. with Synergic Effect of Doxycycline for Anticancer and Bactericidal Activity. Curr. Microbiol. 2020, 77 (9), 2287– 2299, DOI: 10.1007/s00284-020-02058-4Google Scholar47Novel Biosynthesis of Copper Nanoparticles Using Zingiber and Allium sp. with Synergic Effect of Doxycycline for Anticancer and Bactericidal ActivityYaqub, Atif; Malkani, Naila; Shabbir, Arifa; Ditta, Sarwar Allah; Tanvir, Fouzia; Ali, Shaista; Naz, Misbah; Kazmi, Syed Akif Raza; Ullah, RehanCurrent Microbiology (2020), 77 (9), 2287-2299CODEN: CUMIDD; ISSN:0343-8651. (Springer)Copper nanoparticles (CuNPs), due to their cost-effective synthesis, interesting properties, and a wide range of applications in conductive inks, cooling fluids, biomedical field, and catalysis, have attracted the attention of scientific community in recent years. The aim of the present study was to develop and characterize antibacterial and anticancer CuNPs synthesized via chem. and biol. methods, and further synthesize CuNPs conjugated with doxycycline to study their synergic effect. During the chem. synthesis, ascorbic acid was used as a stabilizing agent, while Zingiber officinale and Allium sativum-derived exts. were used during the biol. methods for synthesis of CuNPs. Characterization of CuNPs was performed by transmission electron microscopy (TEM), UV-visible spectroscopy, Fourier transform IR spectroscopy (FTIR), and X-ray crystallog. (XRD). Antimicrobial evaluation of the nanomaterials against Pseudomonas aeruginosa and Escherichia coli was performed by using disk diffusion method, while anticancer behavior against HeLa and HepG2 cell lines was studied by MTT assay. TEM revealed spherical-shaped nanoparticles with mean size of 22.70 ± 5.67, 35.01 ± 5.84, and 19.02 ± 2.41 nm for CuNPs, Gin-CuNPs, and Gar-CuNPs, resp., and surface plasmon resonance peaks were obtained at 570 nm, 575 nm, and 610 nm for CuNPs, Gar-CuNPs, and Gin-CuNPs, resp. The results of FTIR confirmed the consumption of biomols. from the plant exts. for the synthesis of CuNPs. XRD anal. also confirmed synthesis of CuNPs. Doxycycline-conjugated NPs exhibited more antibacterial effects than doxycycline or CuNPs alone. Copper nanoparticles prepd. by biol. synthesis are cost-effective and eco-friendly as compared to their chem. counterparts. The chem. synthesized nanoparticles displayed more significant antimicrobial activity when capped with doxycycline than Z. officinale and A. sativum-mediated CuNPs; however, green-synthesized nanoparticles showed greater anticancer activity than their chem. counterparts.
- 49Velnar, T.; Bailey, T.; Smrkolj, V. The Wound Healing Process: An Overview of the Cellular and Molecular Mechanisms. J. Int. Med. Res. 2009, 37, 1528– 1542, DOI: 10.1177/147323000903700531Google Scholar48The wound healing process: an overview of the cellular and molecular mechanismsVelnar, T.; Bailey, T.; Smrkolj, V.Journal of International Medical Research (2009), 37 (5), 1528-1542CODEN: JIMRBV; ISSN:0300-0605. (Field House Publishing LLP)A review. Wound healing remains a challenging clin. problem and correct, efficient wound management is essential. Much effort has been focused on wound care with an emphasis on new therapeutic approaches and the development of technologies for acute and chronic wound management. Wound healing involves multiple cell populations, the extracellular matrix and the action of sol. mediators such as growth factors and cytokines. Although the process of healing is continuous, it may be arbitrarily divided into four phases: (i) coagulation and haemostasis; (ii) inflammation; (iii) proliferation; and (iv) wound remodelling with scar tissue formation. The correct approach to wound management may effectively influence the clin. outcome. This review discusses wound classification, the physiol. of the wound healing process and the methods used in wound management.
- 50Kalashnikova, I.; Das, S.; Seal, S. Nanomaterials for Wound Healing: Scope and Advancement. Nanomedicine 2015, 10 (16), 2593– 2612, DOI: 10.2217/nnm.15.82Google Scholar49Nanomaterials for wound healing: scope and advancementKalashnikova, Irina; Das, Soumen; Seal, SudiptaNanomedicine (London, United Kingdom) (2015), 10 (16), 2593-2612CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Innovative methods for treating impaired and hard-to-heal wounds are needed. Novel strategies are needed for faster healing by reducing infection, moisturizing the wound, stimulating the healing mechanisms, speeding up the wound closure and reducing scar formation. In the past few years, nanotechnol. has been constantly revolutionizing the treatment and management of wound care, by offering novel solns. which include but are not limited to: state-of-the-art materials, so called 'smart' biomaterials and theranostic nanoparticles. Nanotechnol.-based therapy has recently announced itself as a possible next-generation therapy that is able to advance wound healing to cure chronic wounds. In this communication, the recent progress in advanced therapy for cutaneous wound healing during last 5 years using a nanotechnol.-based approach is summarized.
- 51Alizadeh, S.; Seyedalipour, B.; Shafieyan, S.; Kheime, A.; Mohammadi, P.; Aghdami, N. Copper Nanoparticles Promote Rapid Wound Healing in Acute Full Thickness Defect via Acceleration of Skin Cell Migration, Proliferation, and Neovascularization. Biochem. Biophys. Res. Commun. 2019, 517 (4), 684– 690, DOI: 10.1016/j.bbrc.2019.07.110Google Scholar50Copper nanoparticles promote rapid wound healing in acute full thickness defect via acceleration of skin cell migration, proliferation, and neovascularizationAlizadeh, Sanaz; Seyedalipour, Bagher; Shafieyan, Saeed; Kheime, Abolfazl; Mohammadi, Parvaneh; Aghdami, NasserBiochemical and Biophysical Research Communications (2019), 517 (4), 684-690CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Worldwide, impaired wound healing leads to a large burden of morbidity and mortality. Current treatments have several limitations. Recently, nanomaterials such as copper nanoparticles (CuNPs) have attracted considerable research interest. Here, we investigated the potential therapeutic effect of various CuNPs concns. (1μM, 10μM, 100μM, 1 mM, and 10 mM) and sizes (20 nm, 40 nm, 80 nm) in wound healing. Our results revealed that the 10μM concn. of 40 nm CuNPs and the 1μM concn. of 80 nm CuNPs were not toxic to the cultured fibroblast, endothelial, and keratinocyte cells, and also 1μM concn. of 80 nm CuNPs enhanced endothelial cell migration and proliferation. Extensive assessment of in-vivo wound healing demonstrated that the 1μM concn. of 80 nm CuNPs accelerated wound healing over a shorter time via formation of granulation tissue and higher new blood vessels. Importantly, serum biochem. anal. confirmed that the 40 nm CuNP (10μM) and 80 nm CuNP (1μM) did not show any accumulation in the liver during wound healing. Overall, our results have indicated that the 1μM concn. of 80 nm CuNPs is a promising NP for wound healing applications without adverse side effects.
- 52Sankar, R.; Baskaran, A.; Shivashangari, K. S.; Ravikumar, V. Inhibition of Pathogenic Bacterial Growth on Excision Wound by Green Synthesized Copper Oxide Nanoparticles Leads to Accelerated Wound Healing Activity in Wistar Albino Rats. J. Mater. Sci.: Mater. Med. 2015, 26, 214, DOI: 10.1007/s10856-015-5543-yGoogle Scholar51Inhibition of pathogenic bacterial growth on excision wound by green synthesized copper oxide nanoparticles leads to accelerated wound healing activity in Wistar Albino ratsSankar Renu; Baskaran Athmanathan; Shivashangari Kanchi Subramanian; Ravikumar VilwanathanJournal of materials science. Materials in medicine (2015), 26 (7), 214 ISSN:.An impaired wound healing is one of the major health related problem in diabetic and non-diabetic patients around the globe. The pathogenic bacteria play a predominant role in delayed wound healing, owing to interaction in the wound area. In our previous work we developed green chemistry mediated copper oxide nanoparticles using Ficus religiosa leaf extract. In the present study we make an attempt to evaluate the anti-bacterial, and wound healing activity of green synthesized copper oxide nanoparticles in male Wistar Albino rats. The agar well diffusion assay revealed copper oxide nanoparticles have substantial inhibition activity against human pathogenic strains such as Klebsiella pneumoniae, Shigella dysenteriae, Staphylococcus aureus, Salmonella typhimurium and Escherichia coli, which were responsible for delayed wound healing process. Furthermore, the analyses results of wound closure, histopathology and protein profiling confirmed that the F. religiosa leaf extract tailored copper oxide nanoparticles have enhanced wound healing activity in Wistar Albino rats.
- 53Zangeneh, M. M.; Ghaneialvar, H.; Akbaribazm, M.; Ghanimatdan, M.; Abbasi, N.; Goorani, S.; Pirabbasi, E.; Zangeneh, A. Novel Synthesis of Falcaria Vulgaris Leaf Extract Conjugated Copper Nanoparticles with Potent Cytotoxicity, Antioxidant, Antifungal, Antibacterial, and Cutaneous Wound Healing Activities under in Vitro and in Vivo Condition. J. Photochem. Photobiol., B 2019, 197, 111556, DOI: 10.1016/j.jphotobiol.2019.111556Google Scholar52Novel synthesis of falcaria vulgaris leaf extract conjugated copper nanoparticles with potent cytotoxicity, antioxidant, antifungal, antibacterial, and cutaneous wound healing activities under in vitro and in vivo conditionZangeneh, Mohammad Mahdi; Ghaneialvar, Hori; Akbaribazm, Mohsen; Ghanimatdan, Mohamad; Abbasi, Naser; Goorani, Samaneh; Pirabbasi, Elham; Zangeneh, AkramJournal of Photochemistry and Photobiology, B: Biology (2019), 197 (), 111556CODEN: JPPBEG; ISSN:1011-1344. (Elsevier B.V.)The aim of this study was green synthesis of copper nanoparticles from aq. ext. of Falcaria vulgaris leaf and assessment of their cytotoxicity, antioxidant, antifungal, antibacterial, and cutaneous wound healing properties. The synthesized CuNPs had great cell viability dose-dependently Investigating the effect of the CuNPs on HUVEC cell line and indicated this method was nontoxic. In part of cutaneous wound healing property of CuNPs, after creating the cutaneous wound, the rats were randomly divided into six groups: treatment with 0.2% CuNPs ointment, treatment with 0.2% CuSO4 ointment, treatment with 0.2% F. vulgaris ointment, treatment with 3% tetracycline ointment, treatment with Eucerin basal ointment, and untreated control. Treatment with CuNPs ointment remarkably increased (p ≤ .01) the wound contracture, vessel, hexosamine, hydroxyl proline, hexuronic acid, fibrocyte, and fibrocytes/fibroblast rate and substantially reduced (p ≤ .01) the wound area, total cells, neutrophil, and lymphocyte compared to other groups. In case of antibacterial effects of CuNPs, they inhibited the growth of all bacteria at 2-8 mg/mL concns. and removed them at 4-16 mg/mL concns. (p ≤ .01). The results of XRD, FT-IR, UV, TEM, and FE-SEM confirm that the aq. ext. of F. vulgaris leaf can be used to yield copper nanoparticles with notable amt. of antioxidant, antifungal, antibacterial, and cutaneous wound healing potentials without any cytotoxicity.
- 54Gopal, A.; Kant, V.; Gopalakrishnan, A.; Tandan, S. K.; Kumar, D. Chitosan-Based Copper Nanocomposite Accelerates Healing in Excision Wound Model in Rats. Eur. J. Pharmacol. 2014, 731 (1), 8– 19, DOI: 10.1016/j.ejphar.2014.02.033Google Scholar53Chitosan-based copper nanocomposite accelerates healing in excision wound model in ratsGopal, Anu; Kant, Vinay; Gopalakrishnan, Anu; Tandan, Surendra K.; Kumar, DineshEuropean Journal of Pharmacology (2014), 731 (), 8-19CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Copper possesses efficacy in wound healing which is a complex phenomenon involving various cells, cytokines and growth factors. Copper nanoparticles modulate cells, cytokines and growth factors involved in wound healing in a better way than copper ions. Chitosan has been shown to be beneficial in healing because of its antibacterial, antifungal, biocompatible and biodegradable polymeric nature. In the present study, chitosan-based copper nanocomposite (CCNC) was prepd. by mixing chitosan and copper nanoparticles. CCNC was applied topically to evaluate its wound healing potential and to study its effects on some important components of healing process in open excision wound model in adult Wistar rats. Significant increase in wound contraction was obsd. in the CCNC-treated rats. The up-regulation of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1(TGF-β1) by CCNC-treatment revealed its role in facilitating angiogenesis, fibroblast proliferation and collagen deposition. The tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were significantly decreased and increased, resp., in CCNC-treated rats. Histol. evaluation showed more fibroblast proliferation, collagen deposition and intact re-epithelialization in CCNC-treated rats. Immunohistochem. of CD31 revealed marked increase in angiogenesis. Thus, we concluded that chitosan-based copper nanocomposite efficiently enhanced cutaneous wound healing by modulation of various cells, cytokines and growth factors during different phases of healing process.
- 55Tao, B.; Lin, C.; Deng, Y.; Yuan, Z.; Shen, X.; Chen, M.; He, Y.; Peng, Z.; Hu, Y.; Cai, K. Copper-Nanoparticle-Embedded Hydrogel for Killing Bacteria and Promoting Wound Healing with Photothermal Therapy. J. Mater. Chem. B 2019, 7 (15), 2534– 2548, DOI: 10.1039/C8TB03272FGoogle Scholar54Copper-nanoparticle-embedded hydrogel for killing bacteria and promoting wound healing with photothermal therapyTao, Bailong; Lin, Chuanchuan; Deng, Yiman; Yuan, Zhang; Shen, Xinkun; Chen, Maowen; He, Ye; Peng, Zhihong; Hu, Yan; Cai, KaiyongJournal of Materials Chemistry B: Materials for Biology and Medicine (2019), 7 (15), 2534-2548CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Bacterial infections at wound tissue sites usually delay the wound healing process and even result in severe life-threatening complications. Therefore, it is imperative to develop an efficient strategy to simultaneously enhance the antibacterial abilities and improve the wound healing process. Here, we report a composite hydrogel composed of methacrylate-modified gelatin (Gel-MA) and N,N-bis(acryloyl)cystamine (BACA)-chelated Cu nanoparticles (Cu NPs) via radical polymn. with a photoinitiator. The Cu NPs could effectively convert NIR laser irradn. (808 nm) energy into localized heat due to the localized surface plasmon resonance (LSPR) effect for effecting photothermal therapy. In vitro antimicrobial expts. revealed that the hybrid hydrogel exhibited predominant antibacterial efficacy against both Gram-pos. (Staphylococcus aureus) and Gram-neg. (Escherichia coli) bacteria, while Cu-NP-embedded hydrogel + laser group exhibited superior antibacterial capacity. The excellent antibacterial properties can be attributed to the synergistic effect of photothermal performance and rapid release of copper ions (Cu2+) because of the laser irradn. of Cu NPs. Moreover, the released Cu2+ could stimulate NIH-3T3 fibroblast proliferation without any inflammatory responses. Moreover, chronic wound healing process of S. aureus-infected model was significantly accelerated with prominent antibacterial ability, reduced inflammatory response, and promoted angiogenesis ability in vivo. In summary, Cu-NP-embedded hydrogels are a promising candidate for skin tissue regeneration and potentially valuable for clin. applications.
- 56Rajendran, N. K.; Kumar, S. S. D.; Houreld, N. N.; Abrahamse, H. A Review on Nanoparticle Based Treatment for Wound Healing. J. Drug Delivery Sci. Technol. 2018, 44, 421– 430, DOI: 10.1016/j.jddst.2018.01.009Google Scholar55A review on nanoparticle based treatment for wound healingRajendran, Naresh Kumar; Kumar, Sathish Sundar Dhilip; Houreld, Nicolette Nadene; Abrahamse, HeidiJournal of Drug Delivery Science and Technology (2018), 44 (), 421-430CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)Wound care management relies mainly on the development of new and effective wound dressing materials, and it continues to be an intense area of research in chronic wound care. Proper wound care management is a significant clin. challenge and there is a growing need for wound care. In recent years, the research and development of wound dressing materials have entered a new level of stds. and there is a far better understanding based on the pathogenesis of chronic wounds. Nanotechnol. offers a superlative approach to hasten the healing of acute and chronic wounds, by stimulating proper movement through the different healing phases. In nanotechnol., the small sized nanomaterials, nanoscaffolds, nanofibers and biomaterials are used for topical drug delivery for wound healing. In recent years, the use of nanomaterials for biomedical and pharmaceutical applications have gained significant attraction. Thus, a considerable percentage of nanomaterials are used in various biomedical applications for wound dressings, drug delivery and other medical purposes. This review is an attempt to illustrate the use of nanoparticles and biodegradable nanomaterials in wound healing. Addnl., the present status of nanoparticles delivery of exogenous growth factors and peptide structures in clin. trials are also reviewed in this manuscript.
- 57Kaplan, J. H.; Maryon, E. B. How Mammalian Cells Acquire Copper: An Essential but Potentially Toxic Metal. Biophys. J. 2016, 110 (1), 7– 13, DOI: 10.1016/j.bpj.2015.11.025Google Scholar56How mammalian cells acquire copper: An essential but potentially toxic metalKaplan, Jack H.; Maryon, Edward B.Biophysical Journal (2016), 110 (1), 7-13CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)A review. Cu is an essential micronutrient, and its role in an array of crit. physiol. processes is receiving increasing attention. Among these are wound healing, angiogenesis, protection against reactive O species, neurotransmitter synthesis, modulation of normal cell and tumor growth, and many others. Free Cu is absent inside cells, and a network of proteins has evolved to deliver this essential, but potentially toxic, metal ion to its intracellular target sites following uptake. Although the total body content is low (∼100 mg), dysfunction of proteins involved in Cu homeostasis results in several well-characterized human disease states. The initial step in cellular Cu handling is its transport across the plasma membrane, a subject of study for only about the last 25 yr. Here, the authors focus on the initial step in Cu homeostasis, the properties of the major protein, hCTR1, that mediates Cu uptake, and the status of the understanding of this highly specialized transport system. Although a high-resoln. structure of the protein is still lacking, an array of biochem. and biophys. studies have provided a picture of how hCTR1 mediates Cu(I) transport and how Cu is delivered to the proteins in the intracellular milieu. Recent studies provide evidence that the transporter also plays a key protective role in the regulation of cellular Cu via regulatory endocytosis, lowering its surface expression, in response to elevated Cu loads.
- 58Ashino, T.; Sudhahar, V.; Urao, N.; Oshikawa, J.; Chen, G. F.; Wang, H.; Huo, Y.; Finney, L.; Vogt, S.; McKinney, R. D.; Maryon, E. B.; Kaplan, J. H.; Ushio-Fukai, M.; Fukai, T. Unexpected Role of the Copper Transporter ATP7A in PDGF-Induced Vascular Smooth Muscle Cell Migration. Circ. Res. 2010, 107 (6), 787– 799, DOI: 10.1161/CIRCRESAHA.110.225334Google Scholar57Unexpected Role of the Copper Transporter ATP7A in PDGF-Induced Vascular Smooth Muscle Cell MigrationAshino, Takashi; Sudhahar, Varadarajan; Urao, Norifumi; Oshikawa, Jin; Chen, Gin-Fu; Wang, Huan; Huo, Yuqing; Finney, Lydia; Vogt, Stefan; McKinney, Ronald D.; Maryon, Edward B.; Kaplan, Jack H.; Ushio-Fukai, Masuko; Fukai, TohruCirculation Research (2010), 107 (6), 787-799CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans-Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation. To det. the role of copper transporter ATP7A in PDGF-induced VSMC migration. Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addn., ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was obsd. by synchrotron-based x-ray fluorescence microscopy at neointimal VSMCs in wire injury model. These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis.
- 59Pickart, L.; Vasquez-Soltero, J. M.; Margolina, A. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. BioMed. Res. Int. 2015, 2015, 648108, DOI: 10.1155/2015/648108Google Scholar58GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin RegenerationPickart Loren; Vasquez-Soltero Jessica Michelle; Margolina AnnaBioMed research international (2015), 2015 (), 648108 ISSN:.GHK (glycyl-L-histidyl-L-lysine) is present in human plasma, saliva, and urine but declines with age. It is proposed that GHK functions as a complex with copper 2+ which accelerates wound healing and skin repair. GHK stimulates both synthesis and breakdown of collagen and glycosaminoglycans and modulates the activity of both metalloproteinases and their inhibitors. It stimulates collagen, dermatan sulfate, chondroitin sulfate, and the small proteoglycan, decorin. It also restores replicative vitality to fibroblasts after radiation therapy. The molecule attracts immune and endothelial cells to the site of an injury. It accelerates wound-healing of the skin, hair follicles, gastrointestinal tract, boney tissue, and foot pads of dogs. It also induces systemic wound healing in rats, mice, and pigs. In cosmetic products, it has been found to tighten loose skin and improve elasticity, skin density, and firmness, reduce fine lines and wrinkles, reduce photodamage, and hyperpigmentation, and increase keratinocyte proliferation. GHK has been proposed as a therapeutic agent for skin inflammation, chronic obstructive pulmonary disease, and metastatic colon cancer. It is capable of up- and downregulating at least 4,000 human genes, essentially resetting DNA to a healthier state. The present review revisits GHK's role in skin regeneration in the light of recent discoveries.
- 60Sen, C. K.; Khanna, S.; Venojarvi, M.; Trikha, P.; Christopher Ellison, E.; Hunt, T. K.; Roy, S. Copper-Induced Vascular Endothelial Growth Factor Expression and Wound Healing. Am. J. Physiol. - Heart Circ. Physiol. 2002, 282 (5), 1821– 1827, DOI: 10.1152/ajpheart.01015.2001Google ScholarThere is no corresponding record for this reference.
- 61Wang, W.; Post, J. I.; Dow, K. E.; Shin, S. H.; Riopelle, R. J.; Ross, G. M. Zinc and Copper Inhibit Nerve Growth Factor-Mediated Protection from Oxidative Stress-Induced Apoptosis. Neurosci. Lett. 1999, 259 (2), 115– 118, DOI: 10.1016/S0304-3940(98)00929-XGoogle Scholar60Zinc and Copper inhibit nerve growth factor-mediated protection from oxidative stress-induced apoptosisWang, Wei; Post, Joan I.; Dow, Kimberly E.; Shin, Seon H.; Riopelle, Richard J.; Ross, Gregory M.Neuroscience Letters (1999), 259 (2), 115-118CODEN: NELED5; ISSN:0304-3940. (Elsevier Science Ireland Ltd.)We have previously provided evidence that two transition metal cations, Zn2+ and Cu2+, can alter the conformation of nerve growth factor (NGF), rendering it unable to bind to its receptors or to activate signal transduction pathways. In the present study, we have assessed the influence of Zn2+ and Cu2+ on NGF-mediated protection from an oxidative insult. Exposure of rat pheochromocytoma (PC12) cells to hydrogen peroxide resulted in an increase in cell death via apoptosis, which was inhibited by NGF. Zn2+ and Cu2+, when added to cultures at a concn. of 100 μM, prevented NGF-mediated survival-promoting effects. Neither of these ions had an effect on basal cell viability (in the absence of NGF) after an oxidative insult. These results demonstrate that Zn2+ and Cu2+ can selectively inhibit NGF-mediated resistance to an oxidative stress, and have significant implications for neuronal function under both physiol. and pathol. (e.g. cerebral ischemia) conditions.
- 62Tahvilian, R.; Zangeneh, M. M.; Falahi, H.; Sadrjavadi, K.; Jalalvand, A. R.; Zangeneh, A. Green Synthesis and Chemical Characterization of Copper Nanoparticles Using Allium Saralicum Leaves and Assessment of Their Cytotoxicity, Antioxidant, Antimicrobial, and Cutaneous Wound Healing Properties. Appl. Organomet. Chem. 2019, 33 (12), e5234, DOI: 10.1002/aoc.5234Google Scholar63Green synthesis and chemical characterization of copper nanoparticles using Allium saralicum leaves and assessment of their cytotoxicity, antioxidant, antimicrobial, and cutaneous wound healing propertiesTahvilian, Reza; Zangeneh, Mohammad Mahdi; Falahi, Homeyra; Sadrjavadi, Komail; Jalalvand, Ali R.; Zangeneh, AkramApplied Organometallic Chemistry (2019), 33 (12), e5234CODEN: AOCHEX; ISSN:0268-2605. (John Wiley & Sons Ltd.)In recent decades, nanotechnol. is growing rapidly owing to its widespread application in science and industry. The aim of the expt. was the green synthesis of copper nanoparticles using Allium saralicum R.M. Fritsch aq. ext. and assessment of their cytotoxicity, antioxidant, antibacterial, antifungal, and cutaneous wound healing effects under in vitro and in vivo conditions. These nanoparticles were characterized by Fourier transformed IR spectroscopy (FT-IR), UV-visible spectroscopy, field emission SEM (FE-SEM), transmission electron microscopy (TEM), and at. force microscopy (AFM). DPPH free radical scavenging test was done to assess the antioxidant properties, which indicated similar antioxidant potentials for CuNPs@Allium and butylated hydroxytoluene. Min. Inhibitory Concn. (MIC), Min. Bactericidal Concn. (MBC), and Min. Fungicidal Concn. (MFC) were specified by macro-broth diln. assay. CuNPs@Allium indicated higher antibacterial and antifungal effects than all std. antibiotics (p ≤ 0.01). Also, CuNPs@Allium inhibited the growth of all bacteria at 1-8 mg/mL concns. and removed them at 2-8 mg/mL concns. (p ≤ 0.01). In the case of antifungal properties of CuNPs@Allium, they prevented the growth of all fungi at 1-4 mg/mL concns. and destroyed them at 2-8 mg/mL concns. (p ≤ 0.01). In vivo expt., after creating the cutaneous wound, the rats were randomly divided into six groups (n = 10): untreated control, treatment with Eucerin basal ointment, treatment with 3% tetracycline ointment, treatment with 0.2% CuSO4 ointment, treatment with 0.2% A. saralicum ointment, and treatment with 0.2% CuNPs@Allium ointment. Use of CuNPs@Allium ointment in the treatment groups substantially reduced (p ≤ 0.01) the wound area, total cells, neutrophil, macrophage, and lymphocyte and remarkably raised (p ≤ 0.01) the wound contracture, hydroxyl proline, hexosamine, hexuronic acid, fibrocyte, and fibrocytes/fibroblast rate compared to other groups. The synthesized CuNPs@Allium had high cell viability dose-dependently (Investigating the effect of the plant on HUVEC cell line) and revealed this method was nontoxic. The results revealed the useful non-cytotoxic, antioxidant, antibacterial, antifungal, and cutaneous wound healing effects of CuNPs@Allium.
- 63Tu, Y.; Lv, M.; Xiu, P.; Huynh, T.; Zhang, M.; Castelli, M.; Liu, Z.; Huang, Q.; Fan, C.; Fang, H.; Zhou, R. Destructive Extraction of Phospholipids from Escherichia coli Membranes by Graphene Nanosheets. Nat. Nanotechnol. 2013, 8 (8), 594– 601, DOI: 10.1038/nnano.2013.125Google Scholar64Destructive extraction of phospholipids from Escherichia coli membranes by graphene nanosheetsTu, Yusong; Lv, Min; Xiu, Peng; Huynh, Tien; Zhang, Meng; Castelli, Matteo; Liu, Zengrong; Huang, Qing; Fan, Chunhai; Fang, Haiping; Zhou, RuhongNature Nanotechnology (2013), 8 (8), 594-601CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Understanding how nanomaterials interact with cell membranes is related to how they cause cytotoxicity and is therefore crit. for designing safer biomedical applications. Recently, graphene (a two-dimensional nanomaterial) was shown to have antibacterial activity on Escherichia coli, but its underlying mol. mechanisms remain unknown. Here we show exptl. and theor. that pristine graphene and graphene oxide nanosheets can induce the degrdn. of the inner and outer cell membranes of Escherichia coli, and reduce their viability. TEM shows three rough stages, and mol. dynamics simulations reveal the at. details of the process. Graphene nanosheets can penetrate into and ext. large amts. of phospholipids from the cell membranes because of the strong dispersion interactions between graphene and lipid mols. This destructive extn. offers a novel mechanism for the mol. basis of graphene's cytotoxicity and antibacterial activity.
- 64Mohandas, A.; Deepthi, S.; Biswas, R.; Jayakumar, R. Chitosan Based Metallic Nanocomposite Scaffolds as Antimicrobial Wound Dressings. Bioactive Materials 2018, 3 (3), 267– 277, DOI: 10.1016/j.bioactmat.2017.11.003Google Scholar65Chitosan based metallic nanocomposite scaffolds as antimicrobial wound dressingsMohandas Annapoorna; Deepthi S; Biswas Raja; Jayakumar RBioactive materials (2018), 3 (3), 267-277 ISSN:.Chitosan based nanocomposite scaffolds have attracted wider applications in medicine, in the area of drug delivery, tissue engineering and wound healing. Chitosan matrix incorporated with nanometallic components has immense potential in the area of wound dressings due to its antimicrobial properties. This review focuses on the different combinations of Chitosan metal nanocomposites such as Chitosan/nAg, Chitosan/nAu, Chitosan/nCu, Chitosan/nZnO and Chitosan/nTiO2 towards enhancement of healing or infection control with special reference to the antimicrobial mechanism of action and toxicity.
- 65Zarrintaj, P.; Moghaddam, A. S.; Manouchehri, S.; Atoufi, Z.; Amiri, A.; Amirkhani, M. A.; Nilforoushzadeh, M. A.; Saeb, M. R.; Hamblin, M. R.; Mozafari, M. Can Regenerative Medicine and Nanotechnology Combine to Heal Wounds? The Search for the Ideal Wound Dressing. Nanomedicine 2017, 12 (19), 2403– 2422, DOI: 10.2217/nnm-2017-0173Google Scholar66Can regenerative medicine and nanotechnology combine to heal wounds? The search for the ideal wound dressingZarrintaj, Payam; Moghaddam, Abolfazl Salehi; Manouchehri, Saeed; Atoufi, Zhaleh; Amiri, Anahita; Amirkhani, Mohammad Amir; Nilforoushzadeh, Mohammad Ali; Saeb, Mohammad Reza; Hamblin, Michael R.; Mozafari, MasoudNanomedicine (London, United Kingdom) (2017), 12 (19), 2403-2422CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)A review. Skin is the outermost covering of the human body and at the same time the largest organ comprising 15% of body wt. and 2 m2 surface area. Skin plays a key role as a barrier against the outer environment depending on its thickness, color and structure, which differ from one site to another. The four major types of problematic wounds include ulcers (diabetic, venous, pressure) and burn wounds. Developing novel dressings helps us to improve the wound healing process in difficult patients. Recent advances in regenerative medicine and nanotechnol. are revolutionizing the field of wound healing. Antimicrobial activity, exogenous cell therapy, growth factor delivery, biodegradable and biocompatible matrix construction, all play a role in hi-tech dressing design. In the present review, we discuss how the principles of regenerative medicine and nanotechnol. can be combined in innovative wound dressings.
- 66Han, G.; Ceilley, R. Chronic Wound Healing: A Review of Current Management and Treatments. Adv. Ther. 2017, 34 (3), 599– 610, DOI: 10.1007/s12325-017-0478-yGoogle Scholar67Chronic Wound Healing: A Review of Current Management and TreatmentsHan George; Ceilley RogerAdvances in therapy (2017), 34 (3), 599-610 ISSN:.Wound healing is a complex, highly regulated process that is critical in maintaining the barrier function of skin. With numerous disease processes, the cascade of events involved in wound healing can be affected, resulting in chronic, non-healing wounds that subject the patient to significant discomfort and distress while draining the medical system of an enormous amount of resources. The healing of a superficial wound requires many factors to work in concert, and wound dressings and treatments have evolved considerably to address possible barriers to wound healing, ranging from infection to hypoxia. Even optimally, wound tissue never reaches its pre-injured strength and multiple aberrant healing states can result in chronic non-healing wounds. This article will review wound healing physiology and discuss current approaches for treating a wound.
- 67Li, J.; Zhai, D.; Lv, F.; Yu, Q.; Ma, H.; Yin, J.; Yi, Z.; Liu, M.; Chang, J.; Wu, C. Preparation of Copper-Containing Bioactive Glass/Eggshell Membrane Nanocomposites for Improving Angiogenesis, Antibacterial Activity and Wound Healing. Acta Biomater. 2016, 36, 254– 266, DOI: 10.1016/j.actbio.2016.03.011Google Scholar68Preparation of copper-containing bioactive glass/eggshell membrane nanocomposites for improving angiogenesis, antibacterial activity and wound healingLi, Jinyan; Zhai, Dong; Lv, Fang; Yu, Qingqing; Ma, Hongshi; Yin, Jinbo; Yi, Zhengfang; Liu, Mingyao; Chang, Jiang; Wu, ChengtieActa Biomaterialia (2016), 36 (), 254-266CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)Effectively stimulating angiogenesis and avoiding wound infection are great challenges in wound care management. Designing new healing dressings with requisite angiogenic capacity and antibacterial performance is of particular significance. In order to achieve this aim, we prepd. a copper (Cu)-contg. bioactive glass nanocoating (40-50 nm) with uniform nanostructure on natural eggshell membrane (Cu-BG/ESM) by the pulsed laser deposition (PLD) technique. The surface physicochem. properties including hydrophilicity and hardness of ESM were significantly improved after depositing Cu-BG nanocoatings. Meanwhile, 5Cu-BG/ESM films contg. 5 mol% Cu stimulated proangiogenesis by improving vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α protein secretion as well as angiogenesis-related gene expression (VEGF, HIF-1α, VEGF receptor 2 (KDR) and endothelial nitric oxide (eNos)) of human umbilical vein endothelial cells (HUVECs). When used to treat full-thickness skin defects in mice, 5Cu-BG/ESM films enhanced the healing quality as confirmed by the significantly improved angiogenesis (as indicated by CD31 expression) and formation of continuous and uniform epidermis layer in vivo. Furthermore, 5Cu-BG/ESM films could maintain a sustained release of Cu2+ ions and distinctly inhibited the viability of bacteria (Escherichia coli). The results indicate that Cu2+ ions released from Cu-BG/ESM nanocomposite films play an important role for improving both angiogenesis and antibacterial activity and the prepd. nanocomposite films combined Cu-contg. BG nanocoatings with ESM are a promising biomaterial for wound healing application. Designing new healing dressings with requisite angiogenic capacity and antibacterial performance is of particular significance in wound care management. In our study, we successfully prepd. copper-contg. bioactive glass/eggshell membrane (Cu-BG/ESM) nanocomposites with uniform bioactive glass nanocoatings by using pulsed laser deposition (PLD) technol. Due to the deposited Cu-BG nanocoatings on the surface of ESM, Cu-BG/ESM nanocomposites possessed significantly improved physicochem. and biol. properties, including surface hydrophilicity, hardness, antibacterial ability, angiogenesis rate in vitro and wound healing quality in vivo as compared to pure ESM and BG/ESM films. Our study showed that prepd. nanocoatings on Cu-BG/ESM nanocomposites offer a beneficial carrier for sustained release of Cu2+ ions which played a key role for improving both angiogenesis and antibacterial activity. The prepd. nanocomposites combined Cu-contg. BG nanocoatings with ESM are a promising biomaterial for wound healing application.
- 68Balcucho, J.; Narváez, D. M.; Castro-Mayorga, J. L. Antimicrobial and Biocompatible Polycaprolactone and Copper Oxide Nanoparticle Wound Dressings against Methicillin-Resistant Staphylococcus aureus. Nanomaterials 2020, 10 (9), 1692, DOI: 10.3390/nano10091692Google Scholar69Antimicrobial and biocompatible polycaprolactone and copper oxide nanoparticlewound dressings against methicillin-resistant Staphylococcus aureusBalcucho, Jennifer; Narvaez, Diana M.; Castro-Mayorga, Jinneth LorenaNanomaterials (2020), 10 (9), 1692CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)One of the major health problems linked to methicillin-resistant Staphylococcus aureus (MRSA) is severe diabetic foot ulcers (DFU), which are assocd. with hospital-acquired infections, lower limb amputations and emerging resistance to the current antibiotics. As an alternative, this work aims to develop a biodegradable and biocompatible material with antimicrobial capacity to prevent DFU. This was achieved by producing active polymeric films with metallic nanoparticles dispersed through a polycaprolactone (PCL) dressing. First, the antimicrobial activity of copper oxide nanoparticles (CuONPs) was tested by the microdilution method, selecting the lowest concn. that has an inhibitory effect on MRSA. Then, active PCL films were prepd. and characterized in terms of their physicochem. properties, antimicrobial performance, cytotoxicity, genotoxicity and hemocompatibility. Active films had chem. and thermal properties like the ones without the antimicrobial agents, which was confirmed through FTIR, Thermogravimetric Anal. (TGA) and Differential Scanning Calorimetry (DSC) anal. In relation to antimicrobial activity, active PCL films inhibited MRSA growth when treated with CuONPs at a concn. of 0.07% (wt./wt.). After exposure to the active film exts., human foreskin fibroblast cells (ATCC SCRC1041) (HFF-1) exhibited a cell viability av. above 80% for all treatments and no DNA damage was found. Finally, PCL films with 0.07% (wt./wt.) CuONPs proved to be hemocompatible, and none of the films evaluated had red blood cell breakage greater than 5%, being within the acceptable limits established by the International Organization for Standardization ISO 10993-4:2002.
- 69Tang, L.; Zhu, L.; Tang, F.; Yao, C.; Wang, J.; Li, L. Mild Synthesis of Copper Nanoparticles with Enhanced Oxidative Stability and Their Application in Antibacterial Films. Langmuir 2018, 34 (48), 14570– 14576, DOI: 10.1021/acs.langmuir.8b02470Google Scholar70Mild Synthesis of Copper Nanoparticles with Enhanced Oxidative Stability and Their Application in Antibacterial FilmsTang, Liangzhen; Zhu, Li; Tang, Fu; Yao, Chuang; Wang, Jie; Li, LidongLangmuir (2018), 34 (48), 14570-14576CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)Copper nanoparticles possess unique phys. and chem. properties; however, their application is often restricted, owing to their tendency to oxidize. In this work, we prepd. copper nanoparticles with enhanced oxidative stability via a simple and low-cost method, where a modified starch was used as an environmentally friendly reducing agent and biocompatible polyethylenimine was used as a stabilizer. The prepd. copper nanoparticles could be stored in air for at least 6 mo without any oxidn. in a dried state. Interestingly, our synthesis could even be performed at room temp. with a longer reaction time. We used various characterization methods to study the reaction mechanism. The prepd. copper nanoparticles were further uniformly doped into an agar film, and this composite showed excellent bacterial killing efficiency, owing to the antibacterial properties of the copper nanoparticles. Our composite film shows potential for various clin. applications, such as wound dressing materials.
- 70Jayaramudu, T.; Varaprasad, K.; Reddy, K. K.; Pyarasani, R. D.; Akbari-Fakhrabadi, A.; Amalraj, J. Chitosan-Pluronic Based Cu Nanocomposite Hydrogels for Prototype Antimicrobial Applications. Int. J. Biol. Macromol. 2020, 143, 825– 832, DOI: 10.1016/j.ijbiomac.2019.09.143Google Scholar72Chitosan-pluronic based Cu nanocomposite hydrogels for prototype antimicrobial applicationsJayaramudu, Tippabattini; Varaprasad, Kokkarachedu; Reddy, K. Koteshwara; Pyarasani, Radha D.; Akbari-Fakhrabadi, A.; Amalraj, JohnInternational Journal of Biological Macromolecules (2020), 143 (), 825-832CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)Copper nanoparticles were synthesized via pptn. technique using the pseudonatural cationic chitosan biopolymer as a stabilizing agent. The nanoparticles developed were successfully incorporated into the 1:1 ratio of blended chitosan: pluronic F127 polymer soln. and made their nanocomposite hydrogels by soln. casting method. The formed copper-based nanocomposite hydrogels were characterized by using Fourier transform IR spectroscopy, thermogravimetric anal., X-ray diffraction, SEM-energy dispersive spectroscopy and transmission electron microscopy studies. The antimicrobial activity of the fabricated nanocomposite hydrogels was tested via an inhibition zone process against both E. coli (gram-neg.) and S. aureus (gram-pos.) bacteria. The results conveyed that the copper-embedded chitosan-pluronic\ F127 nanocomposite hydrogels can be used effectively for antimicrobial applications as well as for wound care applications.
- 71Hanafy, N.; Leporatti, S.; El-Kemary, M. Mucoadhesive Hydrogel Nanoparticles as Smart Biomedical Drug Delivery System. Appl. Sci. 2019, 9 (5), 825, DOI: 10.3390/app9050825Google Scholar73Mucoadhesive hydrogel nanoparticles as smart biomedical drug delivery systemHanafy, Nemany A. N.; Leporatti, Stefano; El-Kemary, Maged A.Applied Sciences (2019), 9 (5), 825CODEN: ASPCC7; ISSN:2076-3417. (MDPI AG)Hydrogels are widely used materials which have many medical applications. Their ability to absorb aq. solns. and biol. fluids gives them innovative characterizations resulting in increased compatibility with biol. activity. In this sense, they are used extensively for encapsulation of several targets such as biomols., viruses, bacteria, and mammalian cells. Indeed, many methods have been published which are used in hydrogel formulation and biomedical encapsulations involving several cross-linkers. This system is still rich with the potential of undiscovered features. The physicochem. properties of polymers, distinguished by their interactions with biol. systems into mucoadhesive, gastro-adhesive, and stimuli responsive polymers. Hydrogel systems may be assembled as tablets, patches, gels, ointments, and films. Their potential to be co-formulated as nanoparticles extends the limits of their assembly and application. In this review, mucoadhesive nanoparticles and their importance for biomedical applications are highlighted with a focus on mechanisms of overcoming mucosal resistance.
- 72Vuković, J. S.; Babić, M. M.; Antić, K. M.; Miljković, M. G.; Perić-Grujić, A. A.; Filipović, J. M.; Tomić, S. L. A High Efficacy Antimicrobial Acrylate Based Hydrogels with Incorporated Copper for Wound Healing Application. Mater. Chem. Phys. 2015, 164, 51– 62, DOI: 10.1016/j.matchemphys.2015.08.022Google Scholar74A high efficacy antimicrobial acrylate based hydrogels with incorporated copper for wound healing applicationVukovic, Jovana S.; Babic, Marija M.; Antic, Katarina M.; Miljkovic, Miona G.; Peric-Grujic, Aleksandra A.; Filipovic, Jovanka M.; Tomic, Simonida Lj.Materials Chemistry and Physics (2015), 164 (), 51-62CODEN: MCHPDR; ISSN:0254-0584. (Elsevier B.V.)In this study, three series of hydrogels based on 2-hydroxyethyl acrylate and itaconic acid, unloaded, with incorporated copper(II) ions and reduced copper, were successfully prepd., characterized and evaluated as novel wound healing materials. Fourier transform IR spectroscopy (FTIR) confirmed the expected structure of obtained hydrogels. SEM (SEM) revealed porous morphol. of unloaded hydrogels, and the morphol. modifications in case of loaded hydrogels. Thermal characteristics were examd. by differential scanning calorimetry (DSC) and the glass transition temps. were obsd. in range of 12-50 °C. Swelling study was conducted in wide range of pHs at 37 °C, confirming pH sensitive behavior for all three series of hydrogels. The in vitro copper release was investigated and the exptl. data were analyzed using several models in order to elucidate the transport mechanism. The antimicrobial assay revealed excellent antimicrobial activity, over 99% against Escherichia coli, Staphylococcus aureus and Candida albicans, as well as good correlation with the copper release expts. In accordance with potential application, water vapor transmission rate, oxygen penetration, dispersion characteristics, fluid retention were obsd. and the suitability of the hydrogels for wound healing application was discussed.
- 73Villanueva, M. E.; Diez, A. M. D. R.; González, J. A.; Pérez, C. J.; Orrego, M.; Piehl, L.; Teves, S.; Copello, G. J. Antimicrobial Activity of Starch Hydrogel Incorporated with Copper Nanoparticles. ACS Appl. Mater. Interfaces 2016, 8 (25), 16280– 16288, DOI: 10.1021/acsami.6b02955Google Scholar75Antimicrobial Activity of Starch Hydrogel Incorporated with Copper NanoparticlesVillanueva, Maria Emilia; Diez, Ana Maria del Rosario; Gonzalez, Joaquin Antonio; Perez, Claudio Javier; Orrego, Manuel; Piehl, Lidia; Teves, Sergio; Copello, Guillermo JavierACS Applied Materials & Interfaces (2016), 8 (25), 16280-16288CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)In order to obtain an antimicrobial gel, a starch-based hydrogel reinforced with silica-coated copper nanoparticles (Cu NPs) was developed. Cu NPs were synthesized by use of a copper salt and hydrazine as a reducing agent. In order to enhance Cu NP stability over time, they were synthesized in a starch medium followed by a silica coating. The starch hydrogel was prepd. by use of urea and water as plasticizers and it was treated with different concns. of silica-coated copper nanoparticles (Si-Cu NPs). The obtained materials were characterized by Fourier transform IR (FT-IR) spectroscopy, ESR (EPR) spectroscopy, SEM (SEM), and rheometry. FT-IR and EPR spectra were used for characterization of Cu NPs and Si-Cu NPs, confirming that a starch cap was formed around the Cu NP and demonstrating the stability of the copper nanoparticle after the silica coating step. SEM images showed Cu NP, Si-Cu NP, and hydrogel morphol. The particle size was polydisperse and the structure of the gels changed along with particle concn. Increased NP content led to larger pores in starch structure. These results were in accordance with the rheol. behavior, where reinforcement by the Si-Cu NP was seen. Antimicrobial activity was evaluated against Gram-neg. (Escherichia coli) and Gram-pos. (Staphylococcus aureus) bacterial species. The hydrogels were demonstrated to maintain antimicrobial activity for at least four cycles of use. A dermal acute toxicity test showed that the material could be scored as slightly irritant, proving its biocompatibility. With these advantages, it is believed that the designed Si-Cu NP loaded hydrogel may show high potential for applications in various clin. fields, such as wound dressings and fillers.
- 74Qiu, H.; Pu, F.; Liu, Z.; Liu, X.; Dong, K.; Liu, C.; Ren, J.; Qu, X. Hydrogel-Based Artificial Enzyme for Combating Bacteria and Accelerating Wound Healing. Nano Res. 2020, 13 (2), 496– 502, DOI: 10.1007/s12274-020-2636-9Google Scholar76Hydrogel-based artificial enzyme for combating bacteria and accelerating wound healingQiu, Hao; Pu, Fang; Liu, Zhengwei; Liu, Xuemeng; Dong, Kai; Liu, Chaoqun; Ren, Jinsong; Qu, XiaogangNano Research (2020), 13 (2), 496-502CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)Artificial enzymes have provided great antimicrobial activity to combat wound infection. However, the lack of tissue repair capability compromised their treatment effect. Therefore, development of novel artificial enzyme concurrently with the excellent antibacterial activity and the property of promoting wound healing are required. Here, we demonstrated the hydrogel-based artificial enzyme composed of copper and amino acids possessed intrinsic peroxidase-like catalytic activity, which could combat wound pathogen effectively and accelerate wound healing by stimulating angiogenesis and collagen deposition. Furthermore, the system possesses good biocompatibility for practical application. The synergic effect of the hydrogel-based artificial enzyme promises the system as a new paradigm in bacteria-infected wound healing therapy.
- 75Cady, N. C.; Behnke, J. L.; Strickland, A. D. Copper-Based Nanostructured Coatings on Natural Cellulose: Nanocomposites Exhibiting Rapid and Efficient Inhibition of a Multi-Drug Resistant Wound Pathogen, A. Baumannii, and Mammalian Cell Biocompatibility in Vitro. Adv. Funct. Mater. 2011, 21 (13), 2506– 2514, DOI: 10.1002/adfm.201100123Google Scholar77Copper-Based Nanostructured Coatings on Natural Cellulose: Nanocomposites Exhibiting Rapid and Efficient Inhibition of a Multi-Drug Resistant Wound Pathogen, A. baumannii, and Mammalian Cell Biocompatibility In VitroCady, Nathaniel C.; Behnke, Jason L.; Strickland, Aaron D.Advanced Functional Materials (2011), 21 (13), 2506-2514CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)This paper describes a layer-by-layer (LBL) electrostatic self-assembly process for fabricating highly efficient antimicrobial nanocoatings on a natural cellulose substrate. The composite materials comprise a chem. modified cotton substrate and a layer of sub-5 nm copper-based nanoparticles. The LBL process involves a chem. preconditioning step to impart high neg. surface charge on the cotton substrate for chelation controlled binding of cupric ions (Cu2+), followed by chem. redn. to yield nanostructured coatings on cotton fibers. These model wound dressings exhibit rapid and efficient killing of a multidrug resistant bacterial wound pathogen, A. baumannii, where an 8-log redn. in bacterial growth can be achieved in as little as 10 min of contact. Comparative silver-based nanocoated wound dressings-a more conventional antimicrobial composite material-exhibit much lower antimicrobial efficiencies; a 5-log redn. in A. baumannii growth is possible after 24 h exposure times to silver nanoparticle-coated cotton substrates. The copper nanoparticle-cotton composites described herein also resist leaching of copper species in the presence of buffer, and exhibit an order of magnitude higher killing efficiency using 20 times less total metal when compared to tests using sol. Cu2+. Together these data suggest that copper-based nanoparticle-coated cotton materials have facile antimicrobial properties in the presence of A. baumannii through a process that may be assocd. with contact killing, and not simply due to enhanced release of metal ion. The biocompatibility of these copper-cotton composites toward embryonic fibroblast stem cells in vitro suggests their potential as a new paradigm in metal-based wound care and combating pathogenic bacterial infections.
- 76Torres, F. G.; Arroyo, J. J.; Troncoso, O. P. Bacterial Cellulose Nanocomposites: An All-Nano Type of Material. Mater. Sci. Eng., C 2019, 98, 1277– 1293, DOI: 10.1016/j.msec.2019.01.064Google Scholar78Bacterial cellulose nanocomposites: An all-nano type of materialTorres, F. G.; Arroyo, J. J.; Troncoso, O. P.Materials Science & Engineering, C: Materials for Biological Applications (2019), 98 (), 1277-1293CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)A review. Bacterial cellulose (BC) is a fascinating polymer with a three-dimensional structure formed by nanofibers of pure cellulose, synthesized by some bacteria and organized as a coherent network. Its biocompatibility and remarkable mech. properties have promoted scientific interest for its use in a variety of applications including biomedical, elec., among others. However, it is the possibility of incorporating nanosized materials into the coherent 3-D network structure displayed by BC what has propelled multiple investigations on the development of BC nanocomposites for different applications. Here we report the different methods and techniques used so far for the BC nanocomposites prodn. We have focused on the processing techniques that allow the incorporation of functional nanoreinforcements, nanofillers and addnl. phases without disturbing the original network structure, leading to the formation of nanomaterials. Processing methods, resulting structure-property relationships and potential applications of these novel nanocomposites are discussed and showcased as a fair example of integrated design and manuf. of materials.
- 77Portela, R.; Leal, C. R.; Almeida, P. L.; Sobral, R. G. Bacterial Cellulose: A Versatile Biopolymer for Wound Dressing Applications. Microb. Biotechnol. 2019, 12 (4), 586– 610, DOI: 10.1111/1751-7915.13392Google Scholar79Bacterial cellulose: a versatile biopolymer for wound dressing applicationsPortela, Raquel; Leal, Catarina R.; Almeida, Pedro L.; Sobral, Rita G.Microbial Biotechnology (2019), 12 (4), 586-610CODEN: MBIIB2; ISSN:1751-7915. (Wiley-Blackwell)A review. Summary : Although several therapeutic approaches are available for wound and burn treatment and much progress has been made in this area, room for improvement still exists, driven by the urgent need of better strategies to accelerate wound healing and recovery, mostly for cases of severe burned patients. Bacterial cellulose (BC) is a biopolymer produced by bacteria with several advantages over vegetal cellulose, such as purity, high porosity, permeability to liq. and gases, elevated water uptake capacity and mech. robustness. Besides its biocompatibility, BC can be modified in order to acquire antibacterial response and possible local drug delivery features. Due to its intrinsic versatility, BC is the perfect example of a biotechnol. response to a clin. problem. In this review, we assess the BC main features and emphasis is given to a specific biomedical application: wound dressings. The prodn. process and the phys.-chem. properties that entitle this material to be used as wound dressing namely for burn healing are highlighted. An overview of the most common BC composites and their enhanced properties, in particular phys. and biol., is provided, including the different prodn. processes. A particular focus is given to the biochem. and genetic manipulation of BC. A summary of the current marketed BC-based wound dressing products is presented, and finally, future perspectives for the usage of BC as wound dressing are foreseen.
- 78Gutierrez, E.; Burdiles, P. A.; Quero, F.; Palma, P.; Olate-Moya, F.; Palza, H. 3D Printing of Antimicrobial Alginate/Bacterial-Cellulose Composite Hydrogels by Incorporating Copper Nanostructures. ACS Biomater. Sci. Eng. 2019, 5 (11), 6290– 6299, DOI: 10.1021/acsbiomaterials.9b01048Google Scholar803D Printing of Antimicrobial Alginate/Bacterial-Cellulose Composite Hydrogels by Incorporating Copper NanostructuresGutierrez, Elena; Burdiles, Patricio A.; Quero, Franck; Palma, Patricia; Olate-Moya, Felipe; Palza, HumbertoACS Biomaterials Science & Engineering (2019), 5 (11), 6290-6299CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)Novel antimicrobial 3D-printed alginate/bacterial-cellulose hydrogels with in situ-synthesized copper nanostructures were developed having improved printability. Prior to 3D printing, two methods were tested for the development of the alginate hydrogels: (a) ionic crosslinking with calcium ions followed by ion exchange with copper ions (method A) and (b) ionic crosslinking with copper ions (method B). A soln. contg. sodium borohydride, used as a reducing agent, was subsequently added to the hydrogels, producing in situ clusters of copper nanoparticles embedded in the alginate hydrogel matrix. The method used and concns. of copper and the reducing agent were found to affect the stability of the alginate/copper hydrogels, with method A producing more stable materials. By increasing the alginate concn. from 1 to 4 wt % and by using method A, alginate/bacterial-cellulose/copper hydrogel structures were 3D-printed having excellent printability as compared with pure alginate hydrogels. It is noteworthy that after redn. with sodium borohydride, the 3D structures presented antimicrobial behavior against Escherichia coli and Staphylococcus aureus strains. Our results introduce a simple route for the prodn. of alginate/cellulose inks with improved behavior toward antimicrobial 3D-printed materials.
- 79Chowdhury, M. N. K.; Beg, M. D. H.; Khan, M. R.; Mina, M. F. Synthesis of Copper Nanoparticles and Their Antimicrobial Performances in Natural Fibres. Mater. Lett. 2013, 98, 26– 29, DOI: 10.1016/j.matlet.2013.02.024Google Scholar81Synthesis of copper nanoparticles and their antimicrobial performances in natural fibresChowdhury, M. N. K.; Beg, M. D. H.; Khan, Maksudur R.; Mina, M. F.Materials Letters (2013), 98 (), 26-29CODEN: MLETDJ; ISSN:0167-577X. (Elsevier B.V.)Copper nanoparticles (CuNPs) were synthesized at ambient atm. condition by the chem. redn. method. The redn. of the soln. of copper chloride salt in the polyvinyl alc. system was done by sodium borohydride soln. The UV-visible spectroscopy, Fourier transformed IR spectroscopy, transmission electron microscopy and X-ray diffraction studies were employed to analyze the formations and sizes of nanoparticles. The av. size of CuNPs was measured to be 3 nm. The synthesized CuNPs were impregnated in natural fibers and their antimicrobial performances were assessed against both the Gram-pos. and Gram-neg. bacteria, showing more antibacterial activity in Escherichia coli than Staphylococcus aureus along with ∼7% antifungal activity.
- 80Valencia, L.; Kumar, S.; Nomena, E. M.; Salazar-Alvarez, G.; Mathew, A. P. In-Situ Growth of Metal Oxide Nanoparticles on Cellulose Nanofibrils for Dye Removal and Antimicrobial Applications. ACS Appl. Nano Mater. 2020, 3 (7), 7172– 7181, DOI: 10.1021/acsanm.0c01511Google Scholar82In-Situ Growth of Metal Oxide Nanoparticles on Cellulose Nanofibrils for Dye Removal and Antimicrobial ApplicationsValencia, Luis; Kumar, Sugam; Nomena, Emma M.; Salazar-Alvarez, German; Mathew, Aji P.ACS Applied Nano Materials (2020), 3 (7), 7172-7181CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)Nanocellulose is known to act as a platform for the in-situ formation of metal oxide nanoparticles, where the multiple components of the resultant hybrids act synergistically toward specific applications. However, typical mineralization reactions require hydrothermal conditions or addn. of further reducing agents. Herein, we demonstrate that carboxylated cellulose nanofibril-based films can spontaneously grow functional metal oxide nanoparticles during the adsorption of heavy metal ions from water, without the need of any further chems. or temp. Despite the apparent universality of this behavior with different metal ions, this work focuses on studying the in-situ formation of copper oxide nanoparticles on TOCNF films as well as the resultant hybrid films with improved functionality toward dye removal from water and antimicrobial activity. Using a combination of cutting-edge techniques (e.g., in-situ SAXS and QCMD) to systematically follow the nanoparticle formation on the nanocellulosic films in real time, we suggest a plausible mechanism of assembly. Our results confirm that carboxylated cellulose nanofibril films act as universal substrate for the formation of metal oxide nanoparticles, and thus hybrid nanomaterials, during metal ion adsorption processes. This phenomenon enables the upcycling of nanocellulosic materials through multistage applications, thus increasing its sustainability and efficiency in terms of an optimal use of resources.
- 81Shahidi, S.; Rashidian, M.; Dorranian, D. Preparation of Antibacterial Textile Using Laser Ablation Method. Opt. Laser Technol. 2018, 99, 145– 153, DOI: 10.1016/j.optlastec.2017.08.025Google Scholar83Preparation of antibacterial textile using laser ablation methodShahidi, Sheila; Rashidian, M.; Dorranian, D.Optics & Laser Technology (2018), 99 (), 145-153CODEN: OLTCAS; ISSN:0030-3992. (Elsevier Ltd.)A facile in situ laser ablation synthesis of copper nanoparticles on cotton fabric is reported in this paper. This synthetic method is a laser ablation based fabrication of Cu nanoparticles on cotton fabric for improved performance and antibacterial activity. The treated cotton fabric was characterized using SEM, energy dispersive X-ray spectroscopy, UV-Visible spectroscopic techniques and antibacterial counting test. Very good antibacterial behavior of treated fabrics achieved. This fabric can be used as medical and industrial textiles.
- 82Sathiyavimal, S.; Vasantharaj, S.; Bharathi, D.; Saravanan, M.; Manikandan, E.; Kumar, S. S.; Pugazhendhi, A. Biogenesis of Copper Oxide Nanoparticles (CuONPs) Using Sida Acuta and Their Incorporation over Cotton Fabrics to Prevent the Pathogenicity of Gram Negative and Gram Positive Bacteria. J. Photochem. Photobiol., B 2018, 188, 126– 134, DOI: 10.1016/j.jphotobiol.2018.09.014Google Scholar84Biogenesis of copper oxide nanoparticles (CuONPs) using Sida acuta and their incorporation over cotton fabrics to prevent the pathogenicity of Gram negative and Gram positive bacteriaSathiyavimal, Selvam; Vasantharaj, Seerangaraj; Bharathi, Devaraj; Saravanan, Mythili; Manikandan, Elayaperumal; Kumar, Smita S.; Pugazhendhi, ArivalaganJournal of Photochemistry and Photobiology, B: Biology (2018), 188 (), 126-134CODEN: JPPBEG; ISSN:1011-1344. (Elsevier B.V.)Textile industry is a major sector providing global financial and employment support to different countries of the world. The major problems of the textile industry are dirt and microbial contaminants affecting the quality of cotton fabrics. Recently, nanoparticles such as silver, chitosan, silicon dioxide, titanium dioxide and zinc oxide have gained attraction in textile industries to avoid the contamination of fabrics through microbes. The necessity to develop an ecofriendly, efficient and cost effective method for the synthesis of nanoparticles is under the radar. Plant exts. serve as potential reducing and coating agents due to the presence of bioactive mols. such as phenols, lipids, carbohydrates, enzymes, protein mols. etc., which endow effective antimicrobial activity to the nanoparticles. In the present study, biol. synthesis of Copper oxide nanoparticles (CuONPs) was performed using S. acuta leaf ext. CuONPs were synthesized and characterized using UV-vis, FTIR, SEM and TEM analyses. The antimicrobial property of CuONPs was tested against Gram neg. (Escherichia coli and Proteus vulgaris) and Gram pos. (Staphylococcus aureus) pathogens, which showed zones of inhibition at different concns. As the final part of the study, CuONPs were coated over cotton fabrics showing longer stability, which prevented the growth of infectious pathogens. Apart from the antimicrobial activity, CuONPs synthesized using S. acuta possessed effective photocatalytic activity against com. dyes.
- 83Marković, D.; Vasiljević, J.; Ašanin, J.; Ilic-Tomic, T.; Tomšič, B.; Jokić, B.; Mitrić, M.; Simončič, B.; Mišić, D.; Radetić, M. The Influence of Coating with Aminopropyl Triethoxysilane and CuO/Cu2O Nanoparticles on Antimicrobial Activity of Cotton Fabrics under Dark Conditions. J. Appl. Polym. Sci. 2020, 137 (40), 49194, DOI: 10.1002/app.49194Google Scholar85The influence of coating with aminopropyl triethoxysilane and CuO/Cu2O nanoparticles on antimicrobial activity of cotton fabrics under dark conditionsMarkovic, Darka; Vasiljevic, Jelena; Asanin, Jelena; Ilic-Tomic, Tatjana; Tomsic, Brigita; Jokic, Bojan; Mitric, Miodrag; Simoncic, Barbara; Misic, Dusan; Radetic, MajaJournal of Applied Polymer Science (2020), 137 (40), 49194CODEN: JAPNAB; ISSN:0021-8995. (John Wiley & Sons, Inc.)A novel impregnation process for the fabrication of cotton nanocomposite with strong antimicrobial activity against antibiotics-resistant bacteria and yeast was developed. The impregnation process includes the sol-gel treatment of fabric with (3-aminopropyl)triethoxysilane in the first step, and synthesis of the CuO/Cu2O nanoparticles (NPs) on the fabric surface in the second step. The in situ synthesis of the CuO/Cu2O NPs was based on the adsorption of Cu2+-ions by the introduced amino groups of the sol-gel coating. The adsorbed Cu2+-ions are subsequently reduced in the alk. soln. of NaBH4. X-ray diffraction measurements confirmed the formation of CuO/Cu2O NPs. SEM and at. absorption spectrometry analyses indicate that the particle size, agglomeration, and amts. of synthesized NPs were highly affected by the initial concn. of CuSO4 soln. The toxicity of nanocomposites to human keratinocytes (HaCaT) and antimicrobial activity against Gram-neg. Escherichia coli ATCC 25922, E. coli ATCC BAA 2469, and Klebsiella pneumoniae ATCC BAA 2146, and Gram-pos. bacteria Staphylococcus aureus ATCC 25923, S. aureus ATCC 43300 and yeast Candida albicans ATCC 24433 strongly depended on the copper content. In addn. to excellent antimicrobial activity, controlled release of Cu2+-ions from the fabrics into physiol. saline soln. was obtained.
- 84Mapanao, A. K.; Santi, M.; Voliani, V. Combined chemo-photothermal treatment of 3D head and neck squamous cell carcinomas by ultrasmall-in-nano gold architectures. J. Colloid Interface Sci. 2021, 582, 1003– 1011, DOI: 10.1016/j.jcis.2020.08.059Google Scholar8600Combined chemo-photothermal treatment of three-dimensional head and neck squamous cell carcinomas by gold nano-architecturesMapanao, Ana Katrina; Santi, Melissa; Voliani, ValerioJournal of Colloid and Interface Science (2021), 582 (Part_B), 1003-1011CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)Synergistic combined treatments are currently practiced in clinics for the management of several neoplasms. While surgery, radiotherapy, and chemotherapy remain as the stds. of care for monomodal and co-treatments, emerging modalities like hyperthermia (HT) demonstrate promising features as (neo)adjuvant, particularly for recurrent cancers. However, the clin. relevance of HT is still debated due to a no. of challenges, such as tumor specific temp. increase, uneven heating of the target, and the lack of agents that concurrently execute HT in combination with radio- and/or chemotherapy. Here, the application of non-persistent ultrasmall-in-nano gold architectures for synergistic chemo-photothermal treatment of head and neck squamous cell carcinomas (HNSCCs) is presented. The nano-architectures are composed of excretable narrow near-IR (NIR)-absorbing gold ultrasmall nanoparticles and an endogenously double controlled cisplatin prodrug. The efficiency of the nano-architectures is evaluated on three-dimensional (3D) models of HNSCCs with pos. or neg. human papillomavirus (HPV) status. The combined treatment causes a more pronounced antitumor action on HPV-pos. HNSCCs. Overall, the findings demonstrate the potential clin. relevance of translatable noble metal-based synergistic treatments in tumors management.
- 85Cassano, D.; Santi, M.; D’Autilia, F.; Mapanao, A. K.; Luin, S.; Voliani, V. Photothermal effect by NIR-responsive excretable ultrasmall-in-nano architectures. Mater. Horiz. 2019, 6, 531– 537, DOI: 10.1039/C9MH00096HGoogle Scholar8601Photothermal effect by NIR-responsive excretable ultrasmall-in-nano architecturesCassano, Domenico; Santi, Melissa; D'Autilia, Francesca; Mapanao, Ana Katrina; Luin, Stefano; Voliani, ValerioMaterials Horizons (2019), 6 (3), 531-537CODEN: MHAOBM; ISSN:2051-6355. (Royal Society of Chemistry)Photothermal therapy (PTT) is a promising (co)treatment with translation potentiality in oncol. Nowadays, the plasmonic nanoparticle-mediated photothermal effect (PT) relies on two well established NIR-responsive platforms: gold nanorods and nanoshells. Nonetheless, these nanostructures are affected by: (i) re-shaping after irradn. that prevents multiple PT treatments, and (ii) severe limitations to clin. translation due to metal persistence issues. Furthermore, evaluation of nanoparticle performance is usually accomplished in vitro or in mouse models, reducing the translational potential of the findings. Here, we report both the straightforward prodn. of narrow-NIR-absorbing gold ultrasmall-in-nano architectures (tNAs) and their suitability as platforms for PT upon CW-irradn. at 808 nm. PT efficiency is fully assessed against 2D cell cultures and customized 3D pancreatic adenocarcinoma models.
- 86Li, L.; Rashidi, L. H.; Yao, M.; Ma, L.; Chen, L.; Zhang, J.; Zhang, Y.; Chen, W. CuS Nanoagents for Photodynamic and Photothermal Therapies: Phenomena and Possible Mechanisms. Photodiagn. Photodyn. Ther. 2017, 19, 5– 14, DOI: 10.1016/j.pdpdt.2017.04.001Google Scholar86CuS nanoagents for photodynamic and photothermal therapies: Phenomena and possible mechanismsLi, Lihua; Rashidi, Leila H.; Yao, Mengyu; Ma, Lun; Chen, Lingling; Zhang, Junying; Zhang, Yu; Chen, WeiPhotodiagnosis and Photodynamic Therapy (2017), 19 (), 5-14CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)Photodynamic therapy (PDT) and photothermal therapy (PTT) have been emerging as attractive and promising methods for tumor treatment in clin. approaches. CuS nanoparticles are effective and cost-effective agents for PTT. Recently, it was obsd. that CuS nanoparticles are also excellence candidates for PDT. However, the mechanisms for CuS nanoparticles as PDT agents have never been discussed. The goal here is to explore the killing mechanisms of CuS nanoparticles as PTT and PDT agents. CuS nanoparticles were synthesized by a simple wet chem. method by coating with amphiphilic polymer and examd. for their therapeutic potential on lung adenocarcinoma cell line SPC-A-1 in vitro and in vivo using a murine cancer model. The CuS nanoparticles produce heat as well as reactive oxygen species (ROS) when excited by 808 nm laser and show strong anticancer effects both in vitro and in vivo. The heating effects and release of copper ions from CuS upon heating in the tumor acidic environments are the main mechanisms for the generation of reactive oxygen species which are lethal bullets for cancer destruction. As a dual-function agent for PTT and PDT, CuS nanoparticles are promising phototherapy agents for cancer treatment.
- 87Li, Y.; Lu, W.; Huang, Q.; Li, C.; Chen, W. Copper Sulfide Nanoparticles for Photothermal Ablation of Tumor Cells. Nanomedicine 2010, 5 (8), 1161– 1171, DOI: 10.2217/nnm.10.85Google Scholar87Copper sulfide nanoparticles for photothermal ablation of tumor cellsLi, Yuebin; Lu, Wei; Huang, Qian; Li, Chun; Chen, WeiNanomedicine (London, United Kingdom) (2010), 5 (8), 1161-1171CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Copper sulfide (CuS) nanoparticles were developed as a new type of agent for photothermal ablation of cancer cells. CuS nanoparticles were synthesized by wet chem. and their application in photothermal ablation of tumor cells was tested by irradn. using a near-IR (NIR) laser beam at 808 nm to elevate the temp. of aq. solns. of CuS nanoparticles as a function of exposure time and nanoparticle concn. CuS nanoparticle-mediated photothermal destruction was evaluated using human cervical cancer HeLa cells with respect to laser dose and nanoparticle concn. Their toxicity was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. CuS nanoparticles have an optical absorption band in the NIR range with a max. absorbance at 900 nm. Irradn. by a NIR laser beam at 808 nm resulted in an increase in the temp. of the CuS nanoparticle aq. soln. as a function of exposure time and nanoparticle concn. CuS nanoparticle-induced photothermal destruction of HeLa cells occurred in a laser dose- and nanoparticle concn.-dependent manner, and displayed minimal cytotoxic effects with a profile similar to that of gold nanoparticles. Owing to their unique optical property, small size, low cost of prodn. and low cytotoxicity, CuS nanoparticles are promising new nanomaterials for cancer photothermal ablation therapy.
- 88Borzenkov, M.; Pallavicini, P.; Taglietti, A.; D’Alfonso, L.; Collini, M.; Chirico, G. Photothermally Active Nanoparticles as a Promising Tool for Eliminating Bacteria and Biofilms. Beilstein J. Nanotechnol. 2020, 11, 1134– 1146, DOI: 10.3762/bjnano.11.98Google Scholar88Photothermally active nanoparticles as a promising tool for eliminating bacteria and biofilmsBorzenkov, Mykola; Pallavicini, Piersandro; Taglietti, Angelo; D'Alfonso, Laura; Collini, Maddalena; Chirico, GiuseppeBeilstein Journal of Nanotechnology (2020), 11 (), 1134-1146CODEN: BJNEAH; ISSN:2190-4286. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A review. Bacterial contamination is a severe issue that affects medical devices, hospital tools and surfaces. When microorganisms adhere to a surface (e.g., medical devices or implants) they can develop into a biofilm, thereby becoming more resistant to conventional biocides and disinfectants. Nanoparticles can be used as an antibacterial agent in medical instruments or as a protective coating in implantable devices. In particular, attention is being drawn to photothermally active nanoparticles that are capable of converting absorbed light into heat. These nanoparticles can efficiently eradicate bacteria and biofilms upon light activation (predominantly near the IR to near-IR spectral region) due a rapid and pronounced local temp. increase. By using this approach new, protective, antibacterial surfaces and materials can be developed that can be remotely activated on demand. In this , we summarize the state-of-the art regarding the application of various photothermally active nanoparticles and their corresponding nanocomposites for the light-triggered eradication of bacteria and biofilms.
- 89Wang, X.; Lv, F.; Li, T.; Han, Y.; Yi, Z.; Liu, M.; Chang, J.; Wu, C. Electrospun Micropatterned Nanocomposites Incorporated with Cu2S Nanoflowers for Skin Tumor Therapy and Wound Healing. ACS Nano 2017, 11 (11), 11337– 11349, DOI: 10.1021/acsnano.7b05858Google Scholar89Electrospun Micropatterned Nanocomposites Incorporated with Cu2S Nanoflowers for Skin Tumor Therapy and Wound HealingWang, Xiaocheng; Lv, Fang; Li, Tian; Han, Yiming; Yi, Zhengfang; Liu, Mingyao; Chang, Jiang; Wu, ChengtieACS Nano (2017), 11 (11), 11337-11349CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Surgical excision of skin cancers can hardly remove the tumor tissues completely and simultaneously result in cutaneous defects. To avoid tumor recurrence and heal the tumor-induced wounds, we designed a tissue engineering membrane possessing bifunctions of tumor therapy and skin tissue regeneration. The micropatterned nanocomposite membrane was successfully fabricated by incorporating Cu2S nanoflowers into biopolymer fibers via a modified electrospinning method. With uniformly embedded Cu2S nanoparticles, the membranes exhibited excellent and controllable photothermal performance under near-IR irradn., which resulted in high mortality (>90%) of skin tumor cells and effectively inhibited tumor growth in mice. Moreover, the membranes supported the adhesion, proliferation, and migration of skin cells as well as significantly stimulated angiogenesis and healed full-thickness skin defects in vivo. This proof-of-concept study offers a facile and reliable strategy for localized skin tumor therapy and tissue regeneration using bifunctional tissue engineering biomaterials, showing great promise for tumor-induced wound healing applications.
- 90Zhou, W.; Zi, L.; Cen, Y.; You, C.; Tian, M. Copper Sulfide Nanoparticles-Incorporated Hyaluronic Acid Injectable Hydrogel With Enhanced Angiogenesis to Promote Wound Healing. Front. Bioeng. Biotechnol. 2020, 8 (8), 417, DOI: 10.3389/fbioe.2020.00417Google Scholar90Copper Sulfide Nanoparticles-Incorporated Hyaluronic Acid Injectable Hydrogel With Enhanced Angiogenesis to Promote Wound HealingZhou Wencheng; Zi Liu; You Chao; Tian Meng; Zhou Wencheng; Cen Ying; Tian Meng; Zi Liu; You Chao; Tian Meng; You Chao; Tian MengFrontiers in bioengineering and biotechnology (2020), 8 (), 417 ISSN:2296-4185.Skin wound caused by trauma, inflammation, surgery, or burns remains a great challenge worldwide since there is no effective therapy available to improve its clinical outcomes. Herein, we report a copper sulfide nanoparticles-incorporated hyaluronic acid (CuS/HA) injectable hydrogel with enhanced angiogenesis to promote wound healing. The prepared hydrogel could not only be injected to the wound site but also exhibited good photothermal effect, with temperature increasing to 50°C from room temperature after 10 min of near-infrared light irradiation. The cell culture experiments also showed that the hydrogel has no cytotoxicity. In the rat skin wound model, the hydrogel treated wounds exhibited better healing performances. Masson's trichrome staining suggested that collagen deposition in wounds treated with the hydrogel was significantly higher than other groups. The immunohistochemical staining showed that the hydrogel can effectively upregulate the expression of vascular endothelial growth factor (VEGF) in the wound area at the incipient stage of healing, and the CD 31 immunofluorescence staining confirmed the enhanced angiogenesis of the hydrogel. Taken together, the prepared CuS/HA hydrogel can effectively increase the collagen deposition, upregulate the expression of VEGF, and enhance the angiogenesis, which may contribute to promote wound healing, making it a promising for application in treating skin wound.
- 91Qiao, Y.; Ping, Y.; Zhang, H.; Zhou, B.; Liu, F.; Yu, Y.; Xie, T.; Li, W.; Zhong, D.; Zhang, Y.; Yao, K.; Santos, H. A.; Zhou, M. Laser-Activatable CuS Nanodots to Treat Multidrug-Resistant Bacteria and Release Copper Ion to Accelerate Healing of Infected Chronic Nonhealing Wounds. ACS Appl. Mater. Interfaces 2019, 11 (4), 3809– 3822, DOI: 10.1021/acsami.8b21766Google Scholar91Laser-Activatable CuS Nanodots to Treat Multidrug-Resistant Bacteria and Release Copper Ion to Accelerate Healing of Infected Chronic Nonhealing WoundsQiao, Yue; Ping, Yuan; Zhang, Hongbo; Zhou, Bo; Liu, Fengyong; Yu, Yinhui; Xie, Tingting; Li, Wanli; Zhong, Danni; Zhang, Yuezhou; Yao, Ke; Santos, Helder A.; Zhou, MinACS Applied Materials & Interfaces (2019), 11 (4), 3809-3822CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)Chronic nonhealing wounds have imposed serious challenges in the clin. practice, esp. for the patients infected with multidrug-resistant microbes. Herein, we developed an ultrasmall copper sulfide (covellite) nanodots (CuS NDs) based dual functional nanosystem to cure multidrug-resistant bacteria-infected chronic nonhealing wound. The nanosystem could eradicate multidrug-resistant bacteria and expedite wound healing simultaneously owing to the photothermal effect and remote control of copper-ion release. The antibacterial results indicated that the combination treatment of photothermal CuS NDs with photothermal effect initiated a strong antibacterial effect for drug-resistant pathogens including methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum β-lactamase Escherichia coli both in vitro and in vivo. Meanwhile, the released Cu2+ could promote fibroblast cell migration and endothelial cell angiogenesis, thus accelerating wound-healing effects. In MRSA-infected diabetic mice model, the nanosystem exhibited synergistic wound healing effect of infectious wounds in vivo and demonstrated negligible toxicity and nonspecific damage to major organs. The combination of ultrasmall CuS NDs with photothermal therapy displayed enhanced therapeutic efficacy for chronic nonhealing wound in multidrug-resistant bacterial infections, which may represent a promising class of antibacterial strategy for clin. translation.
- 92Guo, L.; Yan, D. D.; Yang, D.; Li, Y.; Wang, X.; Zalewski, O.; Yan, B.; Lu, W. Combinatorial Photothermal and Immuno Cancer Therapy Using Chitosan-Coated Hollow Copper Sulfide Nanoparticles. ACS Nano 2014, 8 (6), 5670– 5681, DOI: 10.1021/nn5002112Google Scholar92Combinatorial Photothermal and Immuno Cancer Therapy Using Chitosan-Coated Hollow Copper Sulfide NanoparticlesGuo, Liangran; Yan, Daisy D.; Yang, Dongfang; Li, Yajuan; Wang, Xiaodong; Zalewski, Olivia; Yan, Bingfang; Lu, WeiACS Nano (2014), 8 (6), 5670-5681CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Near-IR light-responsive inorg. nanoparticles have been shown to enhance the efficacy of cancer photothermal ablation therapy. However, current nanoparticle-mediated photothermal ablation is more effective in treating local cancer at the primary site than metastatic cancer. Here, we report the design of a near-IR light-induced transformative nanoparticle platform that combines photothermal ablation with immunotherapy. The design is based on chitosan-coated hollow CuS nanoparticles that assemble the immunoadjuvants oligodeoxynucleotides contg. the cytosine-guanine (CpG) motifs. Interestingly, these structures break down after laser excitation, reassemble, and transform into polymer complexes that improve tumor retention of the immunotherapy. In this "photothermal immunotherapy" approach, photothermal ablation-induced tumor cell death reduces tumor growth and releases tumor antigens into the surrounding milieu, while the immunoadjuvants potentiate host antitumor immunity. Our results indicated that combined photothermal immunotherapy is more effective than either immunotherapy or photothermal therapy alone against primary treated and distant untreated tumors in a mouse breast cancer model. These hollow CuS nanoparticles are biodegradable and can be eliminated from the body after laser excitation.
- 93Yin, M.; Li, Z.; Ju, E.; Wang, Z.; Dong, K.; Ren, J.; Qu, X. Multifunctional Upconverting Nanoparticles for Near-Infrared Triggered and Synergistic Antibacterial Resistance Therapy. Chem. Commun. 2014, 50 (72), 10488– 10490, DOI: 10.1039/C4CC04584JGoogle Scholar93Multifunctional upconverting nanoparticles for near-infrared triggered and synergistic antibacterial resistance therapyYin, Meili; Li, Zhenhua; Ju, Enguo; Wang, Zhenzhen; Dong, Kai; Ren, Jinsong; Qu, XiaogangChemical Communications (Cambridge, United Kingdom) (2014), 50 (72), 10488-10490CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)To integrate photodynamic therapy with photothermal therapy for improved multidrug-resistant bacteria therapy, we have constructed a novel multifunctional core/satellite nanostructure by decorating CuS nanoparticles onto the surface of NaYF4:Mn/Yb/Er@photosensitizer doped SiO2. This system exhibited a superior antibacterial activity towards drug-resistant Staphylococcus aureus and Escherichia coli.
- 94Yugandhar, P.; Vasavi, T.; Jayavardhana Rao, Y.; Uma Maheswari Devi, P.; Narasimha, G.; Savithramma, N. Cost Effective, Green Synthesis of Copper Oxide Nanoparticles Using Fruit Extract of Syzygium Alternifolium (Wt.) Walp., Characterization and Evaluation of Antiviral Activity. J. Cluster Sci. 2018, 29 (4), 743– 755, DOI: 10.1007/s10876-018-1395-1Google Scholar94Cost Effective, Green Synthesis of Copper Nanoparticles Using Fruit Extract of Syzygium alternifolium (Wt.) Walp., Characterization and Evaluation of Antiviral ActivityYugandhar, Pulicherla; Vasavi, Thirumalanadhuni; Jayavardhana Rao, Yagani; Uma Maheswari Devi, Palempalli; Narasimha, Golla; Savithramma, NataruJournal of Cluster Science (2018), 29 (4), 743-755CODEN: JCSCEB; ISSN:1040-7278. (Springer)The present study was aimed to synthesize copper oxide nanoparticles (CuO NPs) using fruit ext. of Syzygium alternifolium and to evaluate their antiviral activity against Newcastle Disease Virus (NDV). The CuO NPs synthesized, were characterized by employing different spectroscopic and microscopic tools. The peak manifested at 285 nm in UV-Vis anal. confirms the synthesis of CuO NPs. FTIR anal. showed two conspicuous peaks at 3253 and 1461 cm-1 which correspond to O-H stretch of phenols and N-H bond of primary amines of proteins resp. This result confirms their involvement in capping and stabilization of nanoparticles. The DLS and zeta potential studies revealed 61.1 nm av. size and - 49.2 mV of zeta potential (ζ) value. The XRD crystallog. investigations exhibited end-centered monoclinic cryst. nature nanoparticles with 17.5 nm av. size. The microscopic (AFM, SEM, TEM) analzses unveiled spherical shaped particles with 2-69 nm size of the CuO NPs. These nanoparticles were settled in poly-dispersed and non-agglomerated state. They exhibited potential growth inhibitory effect on NDV virus. Based on the results of present work it can be emphasized that nanoparticles synthesized using plant exts. find a place in future nanomedicine.
- 95Tavakoli, A.; Hashemzadeh, M. S. Inhibition of Herpes Simplex Virus Type 1 by Copper Oxide Nanoparticles. J. Virol. Methods 2020, 275, 113688, DOI: 10.1016/j.jviromet.2019.113688Google Scholar95Inhibition of herpes simplex virus type 1 by copper oxide nanoparticlesTavakoli, Ahmad; Hashemzadeh, Mohammad SadeghJournal of Virological Methods (2020), 275 (), 113688CODEN: JVMEDH; ISSN:0166-0934. (Elsevier B.V.)There are accumulating reports of the emergence of drug-resistant strains of HSV-1 that have become a barrier to successful treatment of HSV-1 infection. Therefore, there is a pressing need to identify and evaluate alternative antiherpetic agents. The aim of the present study was to investigate the effect of copper oxide nanoparticles (CuO-NPs) on HSV-1 infection. The MTT assay was applied to examine the cytotoxic effects of CuO-NPs on Vero cells. Antiherpetic potency was detd. using the TCID50 and quant. Real-Time PCR assays. To evaluate the inhibitory impact of CuO-NPs on the expression of viral antigens, an indirect immunofluorescence assay (IFA) was performed. Acyclovir was used as a ref. drug in all expts. Exposure of HSV-1 with CuO-NPs at the highest non-toxic concn. (100 ug/mL) resulted in 2.8 log10 TCID50 redn. in infectious virus titer as compared with virus control (P < 0.0001). This concn. of CuO-NPs was assocd. with 83.3% inhibition rate, which was estd. based on the HSV-1 viral load compared to virus control. Our findings demonstrated that CuO-NPs are assocd. with a significant antiviral potency against HSV-1. This feature shows strong potential for CuO-NPs to be used in topical formulations for the treatment of orolabial or genital herpetic lesions.
- 96Broglie, J. J.; Alston, B.; Yang, C.; Ma, L.; Adcock, A. F.; Chen, W.; Yang, L. Antiviral Activity of Gold/Copper Sulfide Core/Shell Nanoparticles against Human Norovirus Virus-Like Particles. PLoS One 2015, 10, e0141050, DOI: 10.1371/journal.pone.0141050Google Scholar96Antiviral activity of gold/copper sulfide core/shell nanoparticles against human norovirus virus-like particlesBroglie, Jessica Jenkins; Alston, Brittny; Yang, Chang; Ma, Lun; Adcock, Audrey F.; Chen, Wei; Yang, LijuPLoS One (2015), 10 (10), e0141050/1-e0141050/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Human norovirus is a leading cause of acute gastroenteritis worldwide in a plethora of residential and com. settings, including restaurants, schools, and hospitals. Methods for easily detecting the virus and for treating and preventing infection are crit. to stopping norovirus outbreaks, and inactivation via nanoparticles (NPs) is a more universal and attractive alternative to other phys. and chem. approaches. Using norovirus GI.1 (Norwalk) virus-like particles (VLPs) as a model viral system, this study characterized the antiviral activity of Au/CuS core/shell nanoparticles (NPs) against GI.1 VLPs for the rapid inactivation of HuNoV. Inactivation of VLPs (GI.1) by Au/CuS NPs evaluated using an absorbancebased ELISA indicated that treatment with 0.083 μM NPs for 10 min inactivated ∼50% VLPs in a 0.37 μg/mL VLP soln. and 0.83 μM NPs for 10 min completely inactivated the VLPs. Increasing nanoparticle concn. and/or VLP-NP contact time significantly increased the virucidal efficacy of Au/CuS NPs. Changes to the VLP particle morphol., size, and capsid protein were characterized using dynamic light scattering, transmission electron microscopy, and Western blot anal. The strategy reported here provides the first reported proof-of-concept Au/CuS NPs-based virucide for rapidly inactivating human norovirus.
- 97Hang, X.; Peng, H.; Song, H.; Qi, Z.; Miao, X.; Xu, W. Antiviral Activity of Cuprous Oxide Nanoparticles against Hepatitis C Virus in Vitro. J. Virol. Methods 2015, 222, 150– 157, DOI: 10.1016/j.jviromet.2015.06.010Google Scholar97Antiviral activity of cuprous oxide nanoparticles against Hepatitis C Virus in vitroHang, Xiaofeng; Peng, Haoran; Song, Hongyuan; Qi, Zhongtian; Miao, Xiaohui; Xu, WenshengJournal of Virological Methods (2015), 222 (), 150-157CODEN: JVMEDH; ISSN:0166-0934. (Elsevier B.V.)Small mol. inhibitors in combination with or without interferon have improved sustained antiviral responses against Hepatitis C Virus (HCV) infection. Nonetheless, resistance to these inhibitors is expected to emerge rapidly due to the high mutation rate of the virus. Thus, new antiviral drugs, in combination with currently available therapies, are urgently needed to treat HCV infection. In the present study, we evaluated the antiviral efficacy of cuprous oxide nanoparticles (CO-NPs) against HCV in the HCVcc/Huh7.5.1 cell culture system. CO-NPs were able to significantly inhibit the infectivity of HCVcc at a non-cytotoxic concn. In addn., CO-NPs inhibited the entry of HCV pseudoparticle (HCVpp), including genotypes 1a, 1b, and 2a, while no effect on HCV replication was obsd. Further time-of-addn. expt. indicated that CO-NPs blocked HCV infection both at the attachment and entry stages. In conclusion, we report that CO-NPs can act as an anti-HCV agent by targeting the binding of infectious HCV particles to hepatic cells and the virus entry into the cells. These findings suggest that CO-NPs may have novel roles in the treatment of patients with chronic hepatitis C.
- 98Ishida, T. Antiviral Activities of Cu 2+ Ions in Viral Prevention, Replication, RNA Degradation, and for Antiviral Efficacies of Lytic Virus, ROS-Mediated Virus, Copper Chelation. World Sci. News 2018, 99 (May), 148– 168Google Scholar98Antiviral activities of Cu2+ ions in viral prevention, replication, RNA degradation, and for antiviral efficacies of lytic virus, ROS-mediated virus, copper chelationIshida, TsuneoWorld Scientific News (2018), 99 (), 148-168CODEN: WSNOAZ; ISSN:2392-2192. (Scientific Publishing House "DARWIN")Copper has been known for decades that marked changes of micronutrient homeostasis in the host are accompanied by infection or inflammation. Copper levels in the serum are significantly elevated in response to inflammation that copper accumulates at sites of inflammation. Easily oxidized copper oxide nanoparticles (CuONPs) are widely used as catalysts that the ability of CuONPs to reduce bacterial population and virus application is enhanced. The mechanism of copper-mediated inactivation of herpes simplex virus (HSV) is by which cupric ions oxidatively damage biomols. Virus-mediated subjugation and modulation of host lipids during infection that the life cycle of most viruses proceeds through a series of basic steps: binding and internalization, fusion, uncoating, of the viral genome, its replication, assembly of new particles, and budding or release of the newly made viruses. The HIV-1 protein Vpu is an 81-amino-acid (16-kDa) type I which the presence of Vpu leads to the degrdn. of BST-2 via an endosome-lysosome degrdn. pathway. Oxidative degrdn. by a Cu-metalloenzyme, and ubiquitin-mediated degrdn. of cellular proteins were exploited. Copper can disrupt the lytic cycle of the Coccolithovirus. Lysins represent a novel class of anti-infectives derived from bacteriophage which lysins are bacterial cell wall hydrolytic enzymes that selectively and rapidly kill specific bacteria. Regarding copper induced cellular toxicity, several mechanisms have been proposed based on the formations of ROS by free Cu ions as cupric and cuprous ions can participate in redox reactions. ROS (O2-,•OH, OH-), Cu+ and H2O2 play the important roles for viral inactivations. Thujaplicin-copper chelates inhibit influenza virus-induced apoptosis. Pyrrolidine dithiocarbamate as a metal ion binding agent inhibits the activity of the viral proteases of polyprotein processing and RNA replication of HRV. Chelation enables metals are capable of ligand scavenging via complexation, since reverse transcriptase enzyme inhibits the growth and replication of RNA tumor viruses. Thus, copper complex and copper chelation enhance antiviral efficacy.
- 99Borkow, G.; Zhou, S. S.; Page, T.; Gabbay, J. A Novel Anti-Influenza Copper Oxide Containing Respiratory Face Mask. PLoS One 2010, 5 (6), e11295, DOI: 10.1371/journal.pone.0011295Google ScholarThere is no corresponding record for this reference.
- 100Sucipto, T. H.; Churrotin, S.; Setyawati, H.; Kotaki, T.; Martak, F.; Soegijanto, S. Antiviral Activity of Copper(II) Chloride Dihydrate against Dengue Virus Type-2 IN Vero Cell Indones. J. Trop. Infect. Dis. 2017, 6 (4), 84, DOI: 10.20473/ijtid.v6i4.3806Google ScholarThere is no corresponding record for this reference.
- 101Shionoiri, N.; Sato, T.; Fujimori, Y.; Nakayama, T.; Nemoto, M.; Matsunaga, T.; Tanaka, T. Investigation of the Antiviral Properties of Copper Iodide Nanoparticles against Feline Calicivirus. J. Biosci. Bioeng. 2012, 113 (5), 580– 586, DOI: 10.1016/j.jbiosc.2011.12.006Google Scholar101Investigation of the antiviral properties of copper iodide nanoparticles against feline calicivirusShionoiri, Nozomi; Sato, Tetsuya; Fujimori, Yoshie; Nakayama, Tsuruo; Nemoto, Michiko; Matsunaga, Tadashi; Tanaka, TsuyoshiJournal of Bioscience and Bioengineering (2012), 113 (5), 580-586CODEN: JBBIF6; ISSN:1389-1723. (Society for Biotechnology, Japan)This study demonstrated the antiviral properties of copper iodide (CuI) nanoparticles against the non-enveloped virus feline calicivirus (FCV) as a surrogate for human norovirus. The effect of CuI nanoparticles on FCV infectivity to Crandell-Rees feline kidney (CRFK) cells was elucidated. The infectivity of FCV to CRFK cells was greatly reduced by 7 orders of magnitude at 1000 μg ml-1 CuI nanoparticles. At the conditions, ESR (ESR) anal. proved hydroxyl radical prodn. in CuI nanoparticle suspension. Furthermore, amino acid oxidn. in the viral capsid protein of FCV was detd. by nanoflow liq. chromatog.-mass spectrometric (nano LC-MS) anal. The use of CuI nanoparticles showed extremely high antiviral activity against FCV. The high antiviral property of CuI nanoparticles was attributed to Cu+, followed by ROS generation and subsequent capsid protein oxidn. CuI nanoparticles could be proposed as useful sources of a continuous supply of Cu+ ions for efficient virus inactivation. Furthermore, this study brings new insights into toxic actions of copper iodide nanoparticles against viruses.
- 102Escoffery, C. C.; Dunn, I.; Patel, H.; Yan, S.; Shukla, S. A Novel Approach to Antiviral COVID-19 Masks, 2020; https://soe.rutgers.edu/sites/default/files/imce/pdfs/GSET_2020___COVID_Masks.pdf.Google ScholarThere is no corresponding record for this reference.
- 103Shi, M.; De Mesy Bentley, K. L.; Palui, G.; Mattoussi, H.; Elder, A.; Yang, H. The Roles of Surface Chemistry, Dissolution Rate, and Delivered Dose in the Cytotoxicity of Copper Nanoparticles †. Nanoscale 2017, 9, 4739, DOI: 10.1039/C6NR09102DGoogle Scholar103The roles of surface chemistry, dissolution rate, and delivered dose in the cytotoxicity of copper nanoparticlesShi, Miao; de Mesy Bentley, Karen L.; Palui, Goutam; Mattoussi, Hedi; Elder, Alison; Yang, HongNanoscale (2017), 9 (14), 4739-4750CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)The understanding of nanoparticle (NP) cytotoxicity is challenging because of incomplete information about physicochem. changes particles undergo once they come into contact with biol. fluids. It is therefore essential to characterize changes in NP properties to better understand their biol. fate and effects in mammalian cells. In this paper, we present a study on the effect of particle surface oxidn. and dissoln. rates of Cu NPs. Particle dissoln., cell-assocd. Cu doses, and oxidative stress responses in A549 luciferase reporter cells were examd. for Cu NPs modified with mercaptocarboxylic acids with different carbon chain lengths and a thiotic acid appended-PEG ligand (TA). We found that these Cu NPs released ionic species together with small particles upon oxidn. and that surface chem. influenced the morphol. and dissoln. rate. The dissoln. rate was also shown to impact both the cellular Cu dosimetry and assocd. oxidative stress responses. The convergent results from dissoln. and dosimetry measurements demonstrate that both intracellular and extracellular (i.e., NP uptake-independent) release of ionic species from Cu NPs greatly affect the cytotoxicity.
- 104Zheng, K.; Dai, X.; Lu, M.; Hüser, N.; Taccardi, N.; Boccaccini, A. R. Synthesis of Copper-Containing Bioactive Glass Nanoparticles Using a Modified Stöber Method for Biomedical Applications. Colloids Surf., B 2017, 150, 159– 167, DOI: 10.1016/j.colsurfb.2016.11.016Google Scholar104Synthesis of copper-containing bioactive glass nanoparticles using a modified Stober method for biomedical applicationsZheng, Kai; Dai, Xinyi; Lu, Miao; Hueser, Norbert; Taccardi, Nicola; Boccaccini, Aldo. R.Colloids and Surfaces, B: Biointerfaces (2017), 150 (), 159-167CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)Copper (Cu)-contg. bioactive glasses (BGs) are attracting attention for bone regeneration and wound healing since they have bone-bonding capability and potential osteogenesis and angiogenesis properties. In this study, highly dispersed and spherical Cu-contg. bioactive glass nanoparticles (Cu-BGNs) were successfully synthesized via a modified Stober method. The content of incorporated Cu in the particles could be tailored by adjusting the amt. of the added Cu precursor, a procedure that had no significant effects on the morphol. and structural characteristics of the nanoparticles. Cu-BGNs exhibited satisfactory apatite-forming ability, as a large quantity of apatite could form on Cu-BGNs pellets after immersion in simulated body fluid for just 3 days. The incorporation of Cu exhibited pos. effects on the apatite formation. In addn., both Si and Cu ions were released from the Cu-BGN in a sustained manner for at least 14 days in cell culture medium, indicating the potential of the BGN as promising carriers for delivering therapeutic Cu ions. Moreover, Cu-BGNs showed no significant cytotoxicity towards human mesenchymal stem cells and fibroblast cells at concns. of 100, 10 and 1μg/mL. Taken together, the results suggest that Cu-BGNs are promising nanoparticulate fillers to develop nanocomposites for biomedical applications esp. in bone regeneration and wound healing.
- 105Santi, M.; Mapanao, A. K.; Cassano, D.; Vlamidis, Y.; Cappello, V.; Voliani, V. Endogenously-Activated Ultrasmall-in-Nano Theranostics: Assessment on 3D Head and Neck Squamous Cell Carcinomas. Cancers 2020, 12 (5), 1063, DOI: 10.3390/cancers12051063Google Scholar105Endogenously-activated ultrasmall-in-nanotherapeutics: assessment on 3D Head and NeckSquamous Cell CarcinomasSanti, Melissa; Mapanao, Ana Katrina; Cassano, Domenico; Vlamidis, Ylea; Cappello, Valentina; Voliani, ValerioCancers (2020), 12 (5), 1063CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)Neg. or pos. HPV-assocd. Head and Neck Squamous Cell Carcinomas (HNSCCs) are high recurrence neoplasms usually resulting in a poor prognosis, mainly due to metastasis formation. Despite the low overall patient survival rate and the severe side effects, the treatment of choice is still cisplatin-based chemotherapy. Here, we report a straightforward protocol for the prodn. of high throughput 3D models of neg. or pos. HPV-assocd. HNSCCs, together with their employment in the therapeutic evaluation of gold ultrasmall-in-nano architectures comprising an endogenously-activatable cisplatin prodrug. Beyond enhancing the biosafety of cisplatin, our approach paves the way for the establishment of synergistic co-therapies for HNSCCs based on excretable noble metals.
- 106Cassano, D.; Pocoví-Martínez, S.; Voliani, V. Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to Clinics. Bioconjugate Chem. 2018, 29 (1), 4– 16, DOI: 10.1021/acs.bioconjchem.7b00664Google Scholar106Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to ClinicsCassano, Domenico; Pocovi-Martinez, Salvador; Voliani, ValerioBioconjugate Chemistry (2018), 29 (1), 4-16CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Currently, nanomaterials are of widespread use in daily com. products. However, the most-promising and potentially impacting application is in the medical field. In particular, nanosized noble metals hold the promise of shifting the current medical paradigms for the detection and therapy of neoplasms thanks to the: (i) localized surface plasmon resonances (LSPRs), (ii) high electron d., and (iii) suitability for straightforward development of all-in-one nanoplatforms. Nonetheless, there is still no clin. approved noble metal nanomaterial for cancer therapy and diagnostics. The clin. translation of noble metal nanoparticles (NPs) is mainly prevented by the issue of persistence in organism after the medical action. Such persistence increases the likelihood of toxicity and the interference with common medical diagnoses. Size redn. to ultrasmall nanoparticles (USNPs) is a suitable approach to promoting metal excretion by the renal pathway. However, most of the functionalities of NPs are lost or severely altered in USNPs, jeopardizing clin. applications. A ground-breaking advance to jointly combine the appealing behaviors of NPs with metal excretion relies on the ultrasmall-in-nano approach for the design of all-in-one degradable nanoplatforms composed of USNPs. Such nanoarchitectures might lead to the delivery of a novel paradigm for nanotechnol., enabling the translation of noble metal nanomaterials to clinics to treat carcinomas in a less-invasive and more-efficient manner. This Review covers the recent progresses related to this exciting approach. The most-significant nanoarchitectures designed with the ultrasmall-in-nano approach are discussed, and perspectives on these nanoarchitectures are provided.
- 107Armanetti, P.; Pocoví-Martínez, S.; Flori, A.; Avigo, C.; Cassano, D.; Menichetti, L.; Voliani, V. Dual Photoacoustic/Ultrasound Multi-Parametric Imaging from Passion Fruit-Like Nano-Architectures. Nanomedicine 2018, 14 (6), 1787– 1795, DOI: 10.1016/j.nano.2018.05.007Google Scholar107Dual photoacoustic/ultrasound multi-parametric imaging from passion fruit-like nano-architecturesArmanetti, Paolo; Pocovi-Martinez, Salvador; Flori, Alessandra; Avigo, Cinzia; Cassano, Domenico; Menichetti, Luca; Voliani, ValerioNanomedicine (New York, NY, United States) (2018), 14 (6), 1787-1795CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Ultrasound (US) imaging is a well-established diagnostic technique to image soft tissues in real time, while photoacoustic (PA) is an emerging imaging technique employed to collect mol. information. Integration of PA and US imaging provides complementary information enhancing diagnostic accuracy without employing ionizing radiations. The development of contrast agents able to combine PA and US features is pivotal to improve the significance of PAUS imaging and for PAUS-guided treatment of neoplasms. Here, we demonstrate in relevant ex-vivo models that disassembling passion fruit-like nano-architectures (pfNAs) can be employed in PAUS imaging. pfNAs are composed by silica nanocapsules comprising aggregates of com. NIR-dyes-modified polymers and ultrasmall gold nanoparticles. The intrinsic US and PA features of pfNAs have been fully characterized and validated in tissue-mimicking materials and in ex vivo prepns. Moreover, the application of a multi-parametric approach has allowed the increase of information extrapolated from collected images for a fine texture anal.
- 108Cassano, D.; Mapanao, A.-K.; Summa, M.; Vlamidis, Y.; Giannone, G.; Santi, M.; Guzzolino, E.; Pitto, L.; Poliseno, L.; Bertorelli, R.; Voliani, V. Biosafety and Biokinetics of Noble Metals: The Impact of Their Chemical Nature. ACS Appl. Bio Mater. 2019, 2 (10), 4464– 4470, DOI: 10.1021/acsabm.9b00630Google Scholar108Biosafety and Biokinetics of Noble Metals: The Impact of Their Chemical NatureCassano, Domenico; Mapanao, Ana-Katrina; Summa, Maria; Vlamidis, Ylea; Giannone, Giulia; Santi, Melissa; Guzzolino, Elena; Pitto, Letizia; Poliseno, Laura; Bertorelli, Rosalia; Voliani, ValerioACS Applied Bio Materials (2019), 2 (10), 4464-4470CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)Effective excretion of nanostructured noble metals is still one of the most challenging bottlenecks for their employment in clin. practice. Besides the persistence issue, the clin. translation of inorg. nanomaterials is also affected by a bewildering lack of investigations regarding their quant. biokinetics. Here, we have quant. correlated the chem. nature of the three most interesting noble metals for biomedical applications to their biosafety and biokinetics in, resp., zebrafish and murine models. Gold, silver, and platinum ultrasmall-in-nano architectures with comparable size elicit, after i.v. administration, different excretion pathways depending on their intrinsic metallic nature. Understanding the in vivo fate of noble metal nanoparticles is a significant breakthrough to unlock their clin. employment for the establishment of treatments for neoplasms, infectious diseases, and neurol. disorders.
- 109Mapanao, A. K.; Giannone, G.; Summa, M.; Ermini, M. L.; Zamborlin, A.; Santi, M.; Cassano, D.; Bertorelli, R.; Voliani, V. Biokinetics and clearance of inhaled gold ultrasmall-in-nano architectures. Nanoscale Adv. 2020, 2, 3815– 3820, DOI: 10.1039/D0NA00521EGoogle Scholar10900Biokinetics and clearance of inhaled gold ultrasmall-in-nano architecturesMapanao, Ana Katrina; Giannone, Giulia; Summa, Maria; Ermini, Maria Laura; Zamborlin, Agata; Santi, Melissa; Cassano, Domenico; Bertorelli, Rosalia; Voliani, ValerioNanoscale Advances (2020), 2 (9), 3815-3820CODEN: NAADAI; ISSN:2516-0230. (Royal Society of Chemistry)Among an organism's entry portals, the respiratory tract is one of the most promising routes for non-invasive administration of therapeutics for local and systemic delivery. On the other hand, it is the subtlest to protect from environmental pollution and microbial occurrences. Here, the biokinetics, distribution, and clearance trends of gold ultrasmall-in-nano architectures administered through a single intranasal application have been quant. evaluated. Apart from reaching the lung parenchyma, the (bio)degradable nano-architectures are able to translocate as well to secondary organs and be almost completely excreted within 10 days. These findings further support the clin. relevance of plasmonic nanomaterials for oncol. and infectious disease treatment and management. Notably, this investigation also provides crucial information regarding the assocd. risks as a consequence of the pulmonary delivery of nanoparticles.
- 110d’Amora, M.; Cassano, D.; Pocovi-Martinez, S.; Giordani, S.; Voliani, V. Biodistribution and biocompatibility of passion fruit-like nano-architectures in zebrafish. Nanotoxicology 2018, 12, 914– 922, DOI: 10.1080/17435390.2018.1498551Google Scholar10901Biodistribution and biocompatibility of passion fruit-like nano-architectures in zebrafishd'Amora, Marta; Cassano, Domenico; Pocovi-Martinez, Salvador; Giordani, Silvia; Voliani, ValerioNanotoxicology (2018), 12 (8), 914-922CODEN: NANOGK; ISSN:1743-5404. (Taylor & Francis Ltd.)Passion fruit-like nano-architectures (NAs) are all-in-one platforms of increasing interest for the translation of metal nanoparticles into clinics. NAs are nature-inspired disassembling inorg. theranostics, which jointly combine most of the appealing behaviors of noble metal nanoparticles with their potential organism excretion. Despite their unique and promising properties, NAs in vivo interactions and potential adverse effects have not yet been investigated. In this study, we employ zebrafish (Danio Rerio) to assess the development toxicity of NAs as well as their uptake and bioaccumulation at different stages of growth. The evaluation of multiple endpoints related to the toxicity clearly indicates that NAs do not induce mortality, developmental defects, or alterations on the hatching rate and behavior of zebrafish. Moreover, the anal. of nanostructures uptake and biodistribution demonstrates that NAs are successfully internalized and present a specific localization. Overall, our results demonstrate that NAs are able to pass through the embryos chorion and accumulate in specific tissues, exhibiting an impressive biocompatibility.
- 111Yin, S. N.; Liu, Y.; Zhou, C.; Yang, S. Glutathione-Mediated Cu(I)/Cu(II) Complexes: Valence-Dependent Effects on Clearance and in Vivo Imaging Application. Nanomaterials 2017, 7 (6), 132, DOI: 10.3390/nano7060132Google Scholar109Glutathione-mediated Cu(I)/Cu(II) complexes: valence-dependent effects on clearance and in vivo imaging applicationYin, Su-Na; Liu, Yuanyuan; Zhou, Chen; Yang, ShengyangNanomaterials (2017), 7 (6), 132/1-132/10CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)Contrast imaging agents need to be cleared in a reasonable time (less than 72 h), so it is quite urgent to understand the structure, biocompatibility, and metab. features of imaging agents. In this work, luminescent Cu(I)-GSH complex and their deriv. oxidized Cu(II)-GSSG complex have been easily synthesized. Through systematically probing the renal clearance and biodistribution of the as-prepd. copper complexes, we found that Cu(I)-GSH complex revealed much more efficient renal clearance and remarkably lower liver accumulation than that of their oxidn. states, which could be due to strong protein binding of partial forms of Cu(II)-GSSG complex. Besides, we also attempted to incorporate radioactive copper-64 into Cu(I)-GSH complex for the synthesis of radioactive contrast agent. Indeed, the as-prepd. radioactive Cu(I)-GSH complex also showed consistent high efficiency renal excretion, allowing them to be potential PET imaging agents in clin. translation.
- 112Yang, S.; Sun, S.; Zhou, C.; Hao, G.; Liu, J.; Ramezani, S.; Yu, M.; Sun, X.; Zheng, J. Renal Clearance and Degradation of Glutathione-Coated Copper Nanoparticles. Bioconjugate Chem. 2015, 26 (3), 511– 519, DOI: 10.1021/acs.bioconjchem.5b00003Google Scholar110Renal Clearance and Degradation of Glutathione-Coated Copper NanoparticlesYang, Shengyang; Sun, Shasha; Zhou, Chen; Hao, Guiyang; Liu, Jinbin; Ramezani, Saleh; Yu, Mengxiao; Sun, Xiankai; Zheng, JieBioconjugate Chemistry (2015), 26 (3), 511-519CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Degrdn. of inorg. nanoparticles (NPs) into small mol. complexes is often obsd. in the physiol. environment; however, how this process influences renal clearance of inorg. NPs is largely unknown. By systematically comparing renal clearance of degradable luminescent glutathione coated copper NPs (GS-CuNPs) and their dissocd. products, Cu(II)-glutathione disulfide (GSSG) complexes (Cu(II)-GSSG), the authors found that GS-CuNPs were eliminated through the urinary system surprisingly faster and accumulated in the liver much less than their smaller dissocn. counterparts. With assistance of radiochem. and positron emission tomog. (PET) imaging, the authors found that the obsd. "nano size" effect in enhancing renal clearance is attributed to the fact that GS-CuNPs are more resistant to serum protein adsorption than Cu(II)-GSSG. In addn., since dissocn. of GS-CuNPs follows zero-order chem. kinetics, their renal clearance and biodistribution also depend on initial injection doses and their dissocn. processes. Quant. understanding of size effect and other factors involved in renal clearance and biodistribution of degradable inorg. NPs will lay down a foundation for further development of renal-clearable inorg. NPs with minimized nanotoxicity.
- 113Liang, G.; Jin, X.; Qin, H.; Xing, D. Glutathione-Capped, Renal-Clearable CuS Nanodots for Photoacoustic Imaging and Photothermal Therapy. J. Mater. Chem. B 2017, 5 (31), 6366– 6375, DOI: 10.1039/C7TB01517HGoogle Scholar111Glutathione-capped, renal-clearable CuS nanodots for photoacoustic imaging and photothermal therapyLiang, Guohai; Jin, Xudong; Qin, Huan; Xing, DaJournal of Materials Chemistry B: Materials for Biology and Medicine (2017), 5 (31), 6366-6375CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)The development of functional nanomaterials that undergo renal clearance is of fundamental importance to their in vivo biomedical applications. The authors report a one-pot method for the prepn. of ultrasmall copper sulfide nanodots capped with a small natural tripeptide glutathione (GSH-CuS NDs). The GSH-CuS NDs had a hydrodynamic diam. of 5.8 nm, smaller than the reported polymer-coated CuS NDs with similar core sizes, and exhibited strong optical absorption and conversion at the near-IR (NIR) region, leading to a sufficient photohyperthermic effect under the irradn. of a 980. nm laser. In vivo studies showed that the GSH-CuS NDs could induce significant photoacoustic imaging signal enhancement and remarkable photothermal therapy efficacy. Importantly, biodistribution studies and MRI imaging showed that the GSH-CuS NDs could freely circulate in the blood pool without undesirable accumulation in the liver and spleen, and could be naturally removed from the body through renal clearance, making them attractive for practical theranostic applications.
- 114Du, B.; Yu, M.; Zheng, J. Transport and Interactions of Nanoparticles in the Kidneys. Nat. Rev. Mater. 2018, 3, 358– 374, DOI: 10.1038/s41578-018-0038-3Google ScholarThere is no corresponding record for this reference.
- 115Du, B.; Jiang, X.; Das, A.; Zhou, Q.; Yu, M.; Jin, R.; Zheng, J. Glomerular Barrier Behaves as an Atomically Precise Bandpass Filter in a Sub-Nanometre Regime. Nat. Nanotechnol. 2017, 12 (11), 1096– 1102, DOI: 10.1038/nnano.2017.170Google Scholar113Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regimeDu, Bujie; Jiang, Xingya; Das, Anindita; Zhou, Qinhan; Yu, Mengxiao; Jin, Rongchao; Zheng, JieNature Nanotechnology (2017), 12 (11), 1096-1102CODEN: NNAABX; ISSN:1748-3387. (Nature Research)The glomerular filtration barrier is known as a 'size cutoff' slit, which retains nanoparticles or proteins larger than 6-8 nm in the body and rapidly excretes smaller ones through the kidneys. However, in the sub-nanometer size regime, we have found that this barrier behaves as an atomically precise 'bandpass' filter to significantly slow down renal clearance of few-atom gold nanoclusters (AuNCs) with the same surface ligands but different sizes (Au18, Au15 and Au10-11). Compared to Au25 (∼1.0 nm), just few-atom decreases in size result in four- to ninefold redns. in renal clearance efficiency in the early elimination stage, because the smaller AuNCs are more readily trapped by the glomerular glycocalyx than larger ones. This unique in vivo nano-bio interaction in the sub-nanometer regime also slows down the extravasation of sub-nanometer AuNCs from normal blood vessels and enhances their passive targeting to cancerous tissues through an enhanced permeability and retention effect. This discovery highlights the size precision in the body's response to nanoparticles and opens a new pathway to develop nanomedicines for many diseases assocd. with glycocalyx dysfunction.
- 116Han, Y.; Wang, T.; Liu, H.; Zhang, S.; Zhang, H.; Li, M.; Sun, Q.; Li, Z. The Release and Detection of Copper Ions from Ultrasmall Theranostic Cu2-XSe Nanoparticles. Nanoscale 2019, 11 (24), 11819– 11829, DOI: 10.1039/C9NR02884FGoogle Scholar114The release and detection of copper ions from ultrasmall theranostic Cu2-xSe nanoparticlesHan, Yaobao; Wang, Tingting; Liu, Hanghang; Zhang, Shaohua; Zhang, Hao; Li, Mengting; Sun, Qiao; Li, ZhenNanoscale (2019), 11 (24), 11819-11829CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)Nanoscale copper chalcogenides have been widely used in nanomedicine, however, their pharmacokinetics, degrdn., and biol. effects of released copper ions are usually overlooked, which are crucial for their future clin. translation. Herein, we report the in vitro and in vivo release of copper ions from polyvinylpyrrolidone (PVP) functionalized ultrasmall copper selenide (Cu2-xSe) theranostic nanoparticles. We synthesized a Cu2+-specific fluorescent probe (NCM), which can quickly and specifically react with copper ions to exhibit very strong near IR fluorescence. The in vitro study shows that copper ions can be slowly released from Cu2-xSe nanoparticles in aq. soln. with the progress of their oxidn. The release of copper ions from Cu2-xSe nanoparticles in RAW 264.7 murine macrophages is very fast, evidenced by the gradual increase of fluorescence intensity and the diffusion of fluorescence from cytoplasm into nuclei. We also demonstrate the distribution, degrdn., and the metab. of ultrasmall Cu2-xSe nanoparticles by the in vivo fluorescence imaging, the blood routine test, blood biochem. and histol. anal., and the characterization of copper transport and binding proteins. The results show that ultrasmall Cu2-xSe nanoparticles were mainly eliminated through feces and urine from the body within 72 h after i.v. injection, and the released copper ions did not cause severe toxicity. Our research highlights the great potential of copper chalcogenide nanoparticles in nanomedicine.
- 117Feng, W.; Nie, W.; Cheng, Y.; Zhou, X.; Chen, L.; Qiu, K.; Chen, Z.; Zhu, M.; He, C. In Vitro and in Vivo Toxicity Studies of Copper Sulfide Nanoplates for Potential Photothermal Applications. Nanomedicine 2015, 11 (4), 901– 912, DOI: 10.1016/j.nano.2014.12.015Google Scholar115In vitro and in vivo toxicity studies of copper sulfide nanoplates for potential photothermal applicationsFeng, Wei; Nie, Wei; Cheng, Yanhua; Zhou, Xiaojun; Chen, Liang; Qiu, Kexin; Chen, Zhigang; Zhu, Meifang; He, ChuanglongNanomedicine (New York, NY, United States) (2015), 11 (4), 901-912CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Copper sulfide (CuS) has emerged as a promising photothermal agent. However, its potential toxic effects still remained poorly understood. Herein, CuS nanoplates were synthesized for toxicity assessment. The in vitro study indicated that the cell viability decreased when CuS nanoplate concn. was higher than 100 μg/mL. CuS nanoplates caused apparent toxicity to HUVEC and RAW 264.7 cells. For acute toxicity, max. tolerated dose and LD 50 were 8.66 and 54.5 mg/kg, resp. Furthermore, the sub-chronic toxicity test results indicated that there was no obvious effect at tested doses during the test period. The biodistribution study showed that i.v. administrated CuS nanoplates were mainly present in the spleen, liver and lung. Taken together, our results shed light on the rational design of CuS nanomaterials to minimize toxicity, thus providing a useful guideline in selecting CuS as the photothermal agent for cancer therapy.
- 118Dey, A.; Manna, S.; Adhikary, J.; Chattopadhyay, S.; De, S.; Chattopadhyay, D.; Roy, S. Biodistribution and Toxickinetic Variances of Chemical and Green Copper Oxide Nanoparticles in Vitro and in Vivo. J. Trace Elem. Med. Biol. 2019, 55, 154– 169, DOI: 10.1016/j.jtemb.2019.06.012Google Scholar116Biodistribution and toxickinetic variances of chemical and green Copper oxide nanoparticles in vitro and in vivoDey, Aditi; Manna, Subhankar; Adhikary, Jaydeep; Chattopadhyay, Sourav; De, Sriparna; Chattopadhyay, Dipankar; Roy, SomenathJournal of Trace Elements in Medicine and Biology (2019), 55 (), 154-169CODEN: JTEBFO; ISSN:0946-672X. (Elsevier GmbH)In this study, chem. (S1) and green (S2) Copper Oxide nanoparticles (NPs) were synthesized to det. their biodistribution and toxicokinetic variances in vitro and in vivo. Both NPs significantly released Copper ions (Cu) in lymphocytes and were primarily deposited in the mononuclear phagocyte system (MPS) such as the liver and spleen in mice. In particular, S2NPs seemed to be prominently stored in the spleen, whereas the S1NPs were widely stored in more organs including the liver, heart, lungs, kidney and intestine. The circulation in the blood and fecal excretions both showed higher S2NPs contents resp. Measurements of cell viability, Hemolysis assay, Reactive Oxygen Species (ROS) generation, biochem. estn. and apoptotic or necrotic study in lymphocytes after 24 h and measurements of body and organ wt., serum chem. evaluation, cytokines level, protein expressions and histopathol. of Balb/C mice after 15 days indicated significant toxicity difference between the S1NPs and S2NPs. Our observations proved that the NPs physiochem. properties influence toxicity and Biodistribution profiles in vitro and in vivo.
- 119Cholewińska, E.; Ognik, K.; Fotschki, B.; Zduńczyk, Z.; Juśkiewicz, J. Comparison of the Effect of Dietary Copper Nanoparticles and One Copper(II) Salt on the Copper Biodistribution and Gastrointestinal and Hepatic Morphology and Function in a Rat Model. PLoS One 2018, 13 (5), e0197083, DOI: 10.1371/journal.pone.0197083Google Scholar117Comparison of the effect of dietary copper nanoparticles and one copper (II) salt on the copper biodistribution and gastrointestinal and hepatic morphology and function in a rat modelCholewinska, Ewelina; Ognik, Katarzyna; Fotschki, Bartosz; Zdunczyk, Zenon; Juskiewicz, JerzyPLoS One (2018), 13 (5), e0197083/1-e0197083/23CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The aim of the study was to investigate the effect of two forms (CuCO3 (CuS); and Cu nanoparticles (CuNP)) and dosages (std. 6.5 mg/kg (H), half of the std. (L)) of addnl. dietary Cu administered to growing rats on gastrointestinal and hepatic function and morphol. Copper in the form of CuNP vs CuS caused lower Cu faecal/urinal excretion and increased Cu accumulation in the brain tissue. Hepatic high-grade hydropic degeneration and necrotic lesions were obsd. only in the CuNP-H animals. In the lower gut, the dietary application of CuNP stifled bacterial enzymic activity of caecal gut microbiota and resulted in lower SCFA prodn. That diminishing effect of CuNP on caecal microbiota activity was accompanied by a relative increase in the secretion of glycoside hydrolases by bacterial cells. The results showed that in comparison to Cu from CuCO3, Cu nanoparticles to a greater extent were absorbed from the intestine, accumulated in brain tissue, exerted antimicrobial effect in the caecum, and at higher dietary dose caused damages in the liver of rats.
- 120Lei, R.; Yang, B.; Wu, C.; Liao, M.; Ding, R.; Wang, Q. Mitochondrial Dysfunction and Oxidative Damage in the Liver and Kidney of Rats Following Exposure to Copper Nanoparticles for Five Consecutive Days. Toxicol. Res. (Cambridge, U. K.) 2015, 4 (2), 351– 364, DOI: 10.1039/C4TX00156GGoogle Scholar118Mitochondrial dysfunction and oxidative damage in the liver and kidney of rats following exposure to copper nanoparticles for five consecutive daysLei, Ronghui; Yang, Baohua; Wu, Chunqi; Liao, Mingyang; Ding, Rigao; Wang, QuanjunToxicology Research (Cambridge, United Kingdom) (2015), 4 (2), 351-364CODEN: TROEE8; ISSN:2045-4538. (Royal Society of Chemistry)Objective: The goal of the current study was to investigate the mol. mechanisms of copper nanoparticle (CuNP)-induced hepato- and nephrotoxicity by a proteomic anal. that was phenotypically anchored to conventional toxicol. outcomes. Methods: We employed specialized proteomic techniques, namely two-dimensional difference gel electrophoresis coupled with mass spectrometry to analyze the changes in protein expression in rat liver and kidney after 5 days of oral copper nanoparticle administration. Serum biochem. analyses and histopathol. examns. of livers and kidneys of all rats were also performed. Results: All of the results indicated that the adverse effects obsd. in the rats treated with 100 mg kg-1 d-1 nanocopper were less than those induced by 200 mg kg-1 d-1 CuNPs. Exposure to CuNPs at a dose of 200 mg kg-1 d-1 for 5 d can induce overt hepatotoxicity and nephrotoxicity through a mechanism that mainly involves scattered dot hepatocytic necrosis and widespread renal proximal tubule necrosis. In addn., significantly elevated copper accumulation, decreased thiol groups and elevated malondialdehyde levels were also obsd. in the liver and kidney tissues. The perturbed proteins identified in the rat livers and kidneys are mainly involved in the respiratory and energy metabs., antioxidant defense, phase II metab., lipid metab., urea cycle, creatine biosynthesis, intracellular calcium homeostasis, and cytoskeletal organization. No abnormalities were identified in the liver and kidney tissues from the rats treated with 200 mg kg-1 microcopper. Conclusions: The results of this study suggest that mitochondrial dysfunction and oxidative damage may be the initial events in the hepato- and nephrotoxicity of copper nanoparticles. The down-regulation of phase II metabolic enzymes in the liver and the decrease in calcium-binding proteins in the kidney appear to be specific modes of action in these target organs. Our findings offer new directions for future research aiming to identify the specific biomarkers of the hepatotoxicity and nephrotoxicity of copper nanoparticles.
- 121Fahmy, H. M.; Ali, O. A.; Hassan, A. A.; Mohamed, M. A. Biodistribution and Toxicity Assessment of Copper Nanoparticles in the Rat Brain. J. Trace Elem. Med. Biol. 2020, 61, 126505, DOI: 10.1016/j.jtemb.2020.126505Google Scholar119Biodistribution and toxicity assessment of copper nanoparticles in the rat brainFahmy, Heba M.; Ali, Omnia A.; Hassan, Asmaa A.; Mohamed, Maha A.Journal of Trace Elements in Medicine and Biology (2020), 61 (), 126505CODEN: JTEBFO; ISSN:0946-672X. (Elsevier GmbH)The increase in the usage of copper nanoparticles (Cu NPs) in the industrial and medical fields has raised concerns about their possible adverse effects. The present study aims to investigate the potential adverse effects of Cu NPs on the brain of adult male Wistar rats through the estn. of some oxidative stress parameters and acetylcholinesterase (AChE) activity. Cu NPs were prepd. and characterized using different techniques: Dynamic Light Scattering, X-Ray Diffraction, Transmission and SEM, Fourier transform IR Spectroscopy, in addn. to Energy Dispersive X-ray Spectroscopy. Rats were divided into two groups: Cu NPs-treated group (IV injected with 15 mg/kg_13 nm Cu NPs for 2 successive days) and a control group (injected with saline). Rats of the 2 groups were decapitated simultaneously after 48 h of the last injection. The Cu content in different brain areas was analyzed using inductively coupled plasma mass spectrometry. Moreover, the effect of Cu NPs on brain edema was evaluated. The behavior of rats in an open-field was also examd. 24 h post the last injection. Significant increases of Cu content in the cortex, cerebellum, striatum, thalamus and hippocampus were found. Moreover, Cu NPs lead to the induction of oxidative stress condition in the thalamus, hypothamaus and medulla. In addn., Cu NPs induced significant increases in AChE activity in the medulla, hippocampus, striatum besides midbrain. Cu NPs-injected rats showed also decreased exploratory behavior. The results obtained in the present study point to the importance of toxicity assessments in evaluating the efficiency of Cu NPs for the safe implementation in different applications.
- 122Liu, Y.; Gao, Y.; Liu, Y.; Li, B.; Chen, C.; Wu, G. Oxidative Stress and Acute Changes in Murine Brain Tissues after Nasal Instillation of Copper Particles with Different Sizes. J. Nanosci. Nanotechnol. 2014, 14 (6), 4534– 4540, DOI: 10.1166/jnn.2014.8290Google Scholar120Oxidative stress and acute changes in murine brain tissues after nasal instillation of copper particles with different sizesLiu, Yang; Gao, Yuxi; Liu, Ying; Li, Bai; Chen, Chunying; Wu, GangJournal of Nanoscience and Nanotechnology (2014), 14 (6), 4534-4540CODEN: JNNOAR; ISSN:1533-4880. (American Scientific Publishers)We aim to investigate the biol. effects of copper particles on the murine brain and their underlying mechanism after nasal instillation of copper particles. We choose different sizes and different concns. of copper nanoparticles for mice intranasal use. Within one week, the mice were sacrificed. Pathol. lesions of glial cells were detected by immunohistochem. assay. Immunohistochem. assay reveals that glial fibrillary acidic protein (GFAP) increased significantly in all exptl. groups, esp. in nanocopper groups. The ultrastructure of nerve cells was obsd. through TEM, whose results show that there were chromatin congregation and mitochondria shrinkage in the olfactory cells, and that there was increase of endoplasmic reticulum and disassocn. of endoplasmic reticulum ribosomes in hippocampus, particularly in the nanocopper-groups. Oxidative stress indexes were detd. with colorimetric methods. There was no significant increase in the antioxidative enzymes (GPX, GST, SOD) in brain tissues; however, significant increase of malondiadehyde (MDA) contents was only found in the Cu nanoparticle-exposed mice at the high dose of 40 mg per kg body wt. Based on the investigation into the biol. effects of copper nanoparticles (23.5 nm) after intranasal instillation to the mice, we have found that copper particles can indeed enter into the olfactory bulb and then the deeper brain. The inhalation of high dose copper nanoparticles can induce severer lesions of brain in the exptl. mice. The underlying mechanism of copper nanoparticles causing severe brain damage bears little connection with oxidative stress.
- 123Zhang, L.; Ru, B.; Liu, Y.; Li, M.; Li, B.; Wang, L.; Xu, L.; Le Guyader, L.; Chen, C. The Dose-Dependent Toxicological Effects and Potential Perturbation on the Neurotransmitter Secretion in Brain Following Intranasal Instillation of Copper Nanoparticles. Nanotoxicology 2012, 6 (5), 562– 575, DOI: 10.3109/17435390.2011.590906Google Scholar121The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticlesZhang, Lili; Bai, Ru; Liu, Ying; Meng, Li; Li, Bai; Wang, Liming; Xu, Ligeng; Le Guyader, Laurent; Chen, ChunyingNanotoxicology (2012), 6 (5), 562-575CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)Increasing prodn. and application of metallic nanomaterials are likely to result in the release of these particles into the environment. These released nanoparticles may enter into the lungs and the central nervous system (CNS) directly through inhalation, which therefore poses a potential risk to human health. Herein, we focus on the systemic toxicity and potential influence on the neurotransmitter secretion of intranasally instilled copper nanoparticles (23.5 nm) at three different doses. Copper nanoparticle-exposed mice exhibit pathol. lesions at different degrees in certain tissues and esp. in lung tissue as revealed by histopathol. and transmission electron microscopy (TEM) observations. Inductively-coupled plasma mass spectrometry (ICP-MS) results show that the liver, lung and olfactory bulb are the main tissues in which the copper concns. increased significantly after exposure to a higher level of Cu nanoparticles (40 mg/kg of body wt.). The secretion levels of various neurotransmitters changed as well in some brain regions, esp. in the olfactory bulb. Our results indicate that the intranasally instilled copper nanoparticles not only cause the lesions where the copper accumulates, but also affect the neurotransmitter levels in the brain.
- 124Liu, Y.; Gao, Y.; Zhang, L.; Wang, T.; Wang, J.; Jiao, F.; Li, W.; Liu, Y.; Li, Y.; Li, B.; Chai, Z.; Wu, G.; Chen, C. Potential Health Impact on Mice after Nasal Instillation of Nano-Sized Copper Particles and Their Translocation in Mice. J. Nanosci. Nanotechnol. 2009, 9 (11), 6335– 6343, DOI: 10.1166/jnn.2009.1320Google Scholar122Potential health impact on mice after nasal instillation of nano-sized copper particles and their translocation in miceLiu, Yang; Gao, Yuxi; Zhang, Lili; Wang, Tiancheng; Wang, Jiangxue; Jiao, Fang; Li, Wei; Liu, Ying; Li, Yufeng; Li, Bai; Chai, Zhifang; Wu, Gang; Chen, ChunyingJournal of Nanoscience and Nanotechnology (2009), 9 (11), 6335-6343CODEN: JNNOAR; ISSN:1533-4880. (American Scientific Publishers)The purpose of this study is to evaluate the overall toxicity of nasal instilled nanoscale copper particles (23.5 nm) in mice. Pathol. examn., target organs identification, and blood biochem. assay of exptl. mice were carried out in comparison with micro-sized copper particles (17 μm). However, only in the high-dose group of copper nanoparticles (40 mg/kg body wt. instilled for three times in one week), the body wt. of mice were retarded and significant pathol. changes were obsd. There were hydropic degeneration around the central vein and the spotty necrosis of hepatocytes in the liver and swelling in the renal glomerulus, while, severe lesion assocd. with the decreased no. of olfactory cells and the dilapidated laminated structure were also obsd. in the olfactory bulb. The serum biochem. assay also indicated the sign of renal and hepatic lesion. However, there were no obvious pathol. and physiol. damages in the mice after instilling different-sized copper nanoparticles with low dose of 1 mg/kg body wt. The retention and distribution of copper in various tissues show that the liver, kidneys and olfactory bulb are the main accumulated tissues for copper particles, which were detd. by high sensitive element-specific technique of ICP-MS. The copper contents of the liver, kidneys and the olfactory bulb increase significantly at the group of 40 mg/kg compared to the control group, which is in agreement with the histol. changes. Therefore, the data indicate that nasal inhaled copper particles at very high dosage can translocate to other organs and tissues and further induce certain lesions. The present results are helpful to get better understanding of the risk assessment and evaluation for copper nanoparticles.
- 125Pal, A.; Badyal, R. K.; Vasishta, R. K.; Attri, S. V.; Thapa, B. R.; Prasad, R. Biochemical, Histological, and Memory Impairment Effects of Chronic Copper Toxicity: A Model for Non-Wilsonian Brain Copper Toxicosis in Wistar Rat. Biol. Trace Elem. Res. 2013, 153 (1–3), 257– 268, DOI: 10.1007/s12011-013-9665-0Google Scholar123Biochemical, Histological, and Memory Impairment Effects of Chronic Copper Toxicity: A Model for Non-Wilsonian Brain Copper Toxicosis in Wistar RatPal, Amit; Badyal, Rama Kumari; Vasishta, Rakesh Kumar; Attri, Savita Verma; Thapa, Babu Ram; Prasad, RajendraBiological Trace Element Research (2013), 153 (1-3), 257-268CODEN: BTERDG; ISSN:0163-4984. (Springer)Animal models of copper toxicosis rarely exhibit neurol. impairments and increased brain copper accumulation impeding the development of novel therapeutic approaches to treat neurodegenerative diseases having high brain Cu content. The aim of this study was to investigate the effects of i.p. injected copper lactate (0.15 mg Cu/100 g body wt.) daily for 90 days on copper and zinc levels in the liver and hippocampus, on biochem. parameters, and on neurobehavioral functions (by Morris water maze) of male Wistar rats. Copper-administered animals exhibited significantly decreased serum acetylcholinesterase (AChE) activity and impaired neuromuscular coordination and spatial memory compared to control rats. Copper-intoxicated rats showed significant increase in liver and hippocampus copper content (99.1 and 73 % increase, resp.), 40.7 % redn. in hepatic zinc content, and interestingly, 77.1 % increase in hippocampus zinc content with concomitant increase in copper and zinc levels in serum and urine compared to control rats. Massive grade 4 copper depositions and grade 1 copper-assocd. protein in hepatocytes of copper-intoxicated rats were substantiated by rhodanine and orcein stains, resp. Copper-intoxicated rats demonstrated swelling and increase in the no. of astrocytes and copper deposition in the choroid plexus, with degenerated neurons showing pyknotic nuclei and dense eosinophilic cytoplasm. In conclusion, the present study shows the first evidence in vivo that chronic copper toxicity causes impaired spatial memory and neuromuscular coordination, swelling of astrocytes, decreased serum AChE activity, copper deposition in the choroid plexus, neuronal degeneration, and augmented levels of copper and zinc in the hippocampus of male Wistar rats.
- 126Kardos, J.; Héja, L.; Simon, Á.; Jablonkai, I.; Kovács, R.; Jemnitz, K. Copper Signalling: Causes and Consequences 06 Biological Sciences 0601 Biochemistry and Cell Biology. Cell Commun. Signaling 2018, 16, 71, DOI: 10.1186/s12964-018-0277-3Google Scholar124Copper signalling: causes and consequencesKardos, Julianna; Heja, Laszlo; Simon, Agnes; Jablonkai, Istvan; Kovacs, Richard; Jemnitz, KatalinCell Communication and Signaling (2018), 16 (), 71CODEN: CCSEC6; ISSN:1478-811X. (BioMed Central Ltd.)Copper-contg. enzymes perform fundamental functions by activating dioxygen (O2) and therefore allowing chem. energy-transfer for aerobic metab. The copper-dependence of O2 transport, metab. and prodn. of signalling mols. are supported by mol. systems that regulate and preserve tightly-bound static and weakly-bound dynamic cellular copper pools. Disruption of the reducing intracellular environment, characterized by glutathione shortage and ambient Cu(II) abundance drives oxidative stress and interferes with the bidirectional, copper-dependent communication between neurons and astrocytes, eventually leading to various brain disease forms. A deeper understanding of of the regulatory effects of copper on neuro-glia coupling via polyamine metab. may reveal novel copper signalling functions and new directions for therapeutic intervention in brain disorders assocd. with aberrant copper metab.
- 127Shi, Y.; Pilozzi, A. R.; Huang, X. Exposure of CuO Nanoparticles Contributes to Cellular Apoptosis, Redox Stress, and Alzheimer’s Aβ Amyloidosis. Int. J. Environ. Res. Public Health 2020, 17 (3), 1005, DOI: 10.3390/ijerph17031005Google ScholarThere is no corresponding record for this reference.
- 128Zhang, H.; Hao, C.; Qu, A.; Sun, M.; Xu, L.; Xu, C.; Kuang, H. Light-Induced Chiral Iron Copper Selenide Nanoparticles Prevent β-Amyloidopathy in Vivo. Angew. Chem., Int. Ed. 2020, 59 (18), 7131– 7138, DOI: 10.1002/anie.202002028Google Scholar126Light-Induced Chiral Iron Copper Selenide Nanoparticles Prevent β-Amyloidopathy In VivoZhang, Hongyu; Hao, Changlong; Qu, Aihua; Sun, Maozhong; Xu, Liguang; Xu, Chuanlai; Kuang, HuaAngewandte Chemie, International Edition (2020), 59 (18), 7131-7138CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The accumulation and deposition of β-amyloid (Aβ) plaques in the brain is considered a potential pathogenic mechanism underlying Alzheimer's disease (AD). Chiral L/D-FexCuySe nanoparticles (NPs) were fabricated that interfere with the self-assembly of Aβ42 monomers and trigger the Aβ42 fibrils in dense structures to become looser monomers under 808 nm near-IR (NIR) illumination. D-FexCuySe NPs have a much higher affinity for Aβ42 fibrils than L-FexCuySe NPs and chiral Cu2-xSe NPs. The chiral FexCuySe NPs also generate more reactive oxygen species (ROS) than chiral Cu2-xSe NPs under NIR-light irradn. In living MN9D cells, D-NPs attenuate the adhesion of Aβ42 to membranes and neuron loss after NIR treatment within 10 min without the photothermal effect. In-vivo expts. showed that D-FexCuySe NPs provide an efficient protection against neuronal damage induced by the deposition of Aβ42 and alleviate symptoms in a mouse model of AD, leading to the recovery of cognitive competence.
- 129Ahamed, M.; Akhtar, M. J.; Alhadlaq, H. A.; Alrokayan, S. A. Assessment of the Lung Toxicity of Copper Oxide Nanoparticles: Current Status. Nanomedicine 2015, 10 (15), 2365– 2377, DOI: 10.2217/nnm.15.72Google Scholar127Assessment of the lung toxicity of copper oxide nanoparticles: current statusAhamed, Maqusood; Akhtar, Mohd Javed; Alhadlaq, Hisham A.; Alrokayan, Salman A.Nanomedicine (London, United Kingdom) (2015), 10 (15), 2365-2377CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Copper oxide nanoparticles (CuO NPs) are being used in several industrial and com. products. Inhalation is one of the most significant routes of metal oxide NP exposure. Hence, the toxicity of CuO NPs in lung tissues is of great concern. In vitro studies have indicated that CuO NPs induce cytotoxicity, oxidative stress and genetic toxicity in cultivated human lung cells. Leaching of Cu ions, reactive oxygen species generation and autophagy appear to be the underlying mechanisms of Cu NP toxicity in lung cells. In vivo studies on the lung toxicity of CuO NPs are largely lacking. Some studies have shown that intratracheal instillation of CuO NPs induced oxidative stress, inflammation and neoplastic lesions in rats. This review critically assessed the current findings of the toxicity of CuO NPs in the lung.
- 130Sandhya Rani, V.; Kishore Kumar, A.; Kumar, C. P.; Rama Narsimha Reddy, A. Pulmonary Toxicity of Copper Oxide (CuO) Nanoparticles in Rats. J. Med. Sci. 2013, 13 (7), 571– 577, DOI: 10.3923/jms.2013.571.577Google ScholarThere is no corresponding record for this reference.
- 131Huang, Y. C.; Vieira, A.; Huang, K. L.; Yeh, M. K.; Chiang, C. H. Pulmonary Inflammation Caused by Chitosan Microparticles. J. Biomed. Mater. Res., Part A 2005, 75A (2), 283– 287, DOI: 10.1002/jbm.a.30421Google Scholar129Pulmonary inflammation caused by chitosan microparticlesHuang, Y. C.; Vieira, A.; Huang, K. L.; Yeh, M. K.; Chiang, C. H.Journal of Biomedical Materials Research, Part A (2005), 75A (2), 283-287CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Chitosan is a cationic biopolymer derived from chitin with potential therapeutic applications such as controlled drug delivery to mucosal-epithelial surfaces in the body. Inhaled chitosan microparticles (CM), for example, are of potential interest in pulmonary pharmacotherapy. In this context, the authors examine some basic reactions of lung tissue to CM. Inhaled CM (2-10 mg/kg of particles) induce dose-dependent proinflammatory effects in rat lungs; these effects are documented in increases in bronchoalveolar lavage fluid protein (BALF-P) and lactate dehydrogenase activity (BALF-LDH) and increases in lung tissue myeloperoxidase (MPO) activity and leukocyte migration. Overall, the biochem. parameters (i.e., av. of BALF-P, BALF-DH, and MPO) indicate that the inflammation response is 1.8-fold greater than controls without CM; the same inflammation parameters, however, are 1.9-fold lower with CM compared with the proinflammatory effects of lipopolysaccharide (LPS). Cytol. examn. of BALF shows a large infiltration of polymorphonuclear neutrophils to lung tissue: more than a 6-fold increase in this population of inflammatory cells, after inhalation of CM relative to air inhalation controls. Thus, the results indicate that inhaled CM can have significant proinflammatory effects on lung tissues; these effects are mild relative to LPS but need to be considered in the context of therapeutic applications via pulmonary delivery if such concns. of CM are used.
- 132Worthington, K. L. S.; Adamcakova-Dodd, A.; Wongrakpanich, A.; Mudunkotuwa, I. A.; Mapuskar, K. A.; Joshi, V. B.; Allan Guymon, C.; Spitz, D. R.; Grassian, V. H.; Thorne, P. S.; Salem, A. K. Chitosan Coating of Copper Nanoparticles Reduces in Vitro Toxicity and Increases Inflammation in the Lung. Nanotechnology 2013, 24 (39), 395101, DOI: 10.1088/0957-4484/24/39/395101Google Scholar130Chitosan coating of copper nanoparticles reduces in vitro toxicity and increases inflammation in the lungWorthington, Kristan L. S.; Adamcakova-Dodd, Andrea; Wongrakpanich, Amaraporn; Mudunkotuwa, Imali A.; Mapuskar, Kranti A.; Joshi, Vijaya B.; Guymon, C. Allan; Spitz, Douglas R.; Grassian, Vicki H.; Thorne, Peter S.; Salem, Aliasger K.Nanotechnology (2013), 24 (39), 395101/1-395101/10, 10 pp.CODEN: NNOTER; ISSN:1361-6528. (IOP Publishing Ltd.)Despite their potential for a variety of applications, copper nanoparticles induce very strong inflammatory responses and cellular toxicity following aerosolized delivery. Coating metallic nanoparticles with polysaccharides, such as biocompatible and antimicrobial chitosan, has the potential to reduce this toxicity. In this study, copper nanoparticles were coated with chitosan using a newly developed and facile method. The presence of coating was confirmed using XPS, rhodamine tagging of chitosan followed by confocal fluorescence imaging of coated particles and obsd. increases in particle size and zeta potential. Further phys. and chem. characteristics were evaluated using dissoln. and x-ray diffraction studies. The chitosan coating was shown to significantly reduce the toxicity of copper nanoparticles after 24 and 52 h and the generation of reactive oxygen species as assayed by DHE oxidn. after 24 h in vitro. Conversely, inflammatory response, measured using the no. of white blood cells, total protein, and cytokines/chemokines in the bronchoalveolar fluid of mice exposed to chitosan coated vs. uncoated copper nanoparticles, was shown to increase, as was the concn. of copper ions. These results suggest that coating metal nanoparticles with mucoadhesive polysaccharides (e.g. chitosan) could increase their potential for use in controlled release of copper ions to cells, but will result in a higher inflammatory response if administered via the lung.
- 133Cassano, D.; Summa, M.; Pocovi-Martinez, S.; Mapanao, A.-K.; Catelani, T.; Bertorelli, R.; Voliani, V. Biodegradable ultrasmall-in-nano gold architectures: mid-period in vivo biodistribution and excretion assessment. Particle and Particle Systems Characterization 2019, 36, 1800464, DOI: 10.1002/ppsc.201800464Google ScholarThere is no corresponding record for this reference.
- 134Vlamidis, Y.; Voliani, V. Bringing again noble metal nanoparticles to the forefront of cancer therapy. Front. Bioeng. Biotechnol. 2018, 6 DOI: 10.3389/fbioe.2018.00143 .Google ScholarThere is no corresponding record for this reference.
- 135Santi, M.; Maccari, G.; Mereghetti, P.; Voliani, V.; Rocchiccioli, S.; Ucciferri, N.; Luin, S.; Signore, G. Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization. Bioconjugate Chem. 2017, 28 (2), 471– 480, DOI: 10.1021/acs.bioconjchem.6b00611Google Scholar131Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle InternalizationSanti, Melissa; Maccari, Giuseppe; Mereghetti, Paolo; Voliani, Valerio; Rocchiccioli, Silvia; Ucciferri, Nadia; Luin, Stefano; Signore, GiovanniBioconjugate Chemistry (2017), 28 (2), 471-480CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chem. derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quant. structure-activity and relationship (QSAR) anal. and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.
- 136Barbero, F.; Russo, L.; Vitali, M.; Piella, J.; Salvo, I.; Borrajo, M. L.; Busquets-Fité, M.; Grandori, R.; Bastús, N. G.; Casals, E.; Puntes, V. Formation of the Protein Corona: The Interface between Nanoparticles and the Immune System. Semin. Immunol. 2017, 34, 52– 60, DOI: 10.1016/j.smim.2017.10.001Google Scholar132Formation of the protein corona: the interface between nanoparticles and the immune systemBarbero, Francesco; Russo, Lorenzo; Vitali, Michele; Piella, Jordi; Salvo, Ignacio; Borrajo, Mireya L.; Busquets-Fite, Marti; Grandori, Rita; Bastus, Neus G.; Casals, Eudald; Puntes, VictorSeminars in Immunology (2017), 34 (), 52-60CODEN: SEIME2; ISSN:1044-5323. (Elsevier Ltd.)The interaction of inorg. nanoparticles and many biol. fluids often withstands the formation of a Protein Corona enveloping the nanoparticle. This Protein Corona provides the biol. identity to the nanoparticle that the immune system will detect. The formation of this Protein Corona depends not only on the compn. of the nanoparticle, its size, shape, surface state and exposure time, but also on the type of media, nanoparticle to protein ratio and the presence of ions and other mol. species that interfere in the interaction between proteins and nanoparticles. This has important implications on immune safety, biocompatibility and the use of nanoparticles in medicine.
- 137Nienhaus, K.; Nienhaus, G. U. Protein Corona around Nanoparticles—Recent Advances and Persisting Challenges. Curr. Opin. Biomed. Eng. 2019, 10, 11– 22, DOI: 10.1016/j.cobme.2019.01.002Google ScholarThere is no corresponding record for this reference.
- 138Akhuli, A.; Chakraborty, D.; Agrawal, A. K.; Sarkar, M. Probing the Interaction of Bovine Serum Albumin with Copper Nanoclusters: Realization of Binding Pathway Different from Protein Corona. Langmuir 2021, 37, 1823, DOI: 10.1021/acs.langmuir.0c03176Google Scholar134Probing the Interaction of Bovine Serum Albumin with Copper Nanoclusters: Realization of Binding Pathway Different from Protein CoronaAkhuli, Amit; Chakraborty, Debabrata; Agrawal, Aman Kumar; Sarkar, MoloyLangmuir (2021), 37 (5), 1823-1837CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)With an aim to understand the interaction mechanism of bovine serum albumin (BSA) with copper nanoclusters (CuNCs), three different types CuNCs having chem. different surface ligands, namely, tannic acid (TA), chitosan, and cysteine (Cys), have been fabricated, and investigations are carried out in the absence and presence of protein (BSA) at ensemble-averaged and single-mol. levels. The CuNCs, capped with different surface ligands, are consciously chosen so that the role of surface ligands in the overall protein-NCs interactions is clearly understood, but, more importantly, to find whether these CuNCs can interact with protein in a new pathway without forming the "protein corona", which otherwise has been obsd. in relatively larger nanoparticles when they are exposed to biol. fluids. Anal. of the data obtained from fluorescence, ζ-potential, and ITC measurements has clearly indicated that the BSA protein in the presence of CuNCs does not attain the binding stoichiometry (BSA/CuNCs > 1) that is required for the formation of "protein corona". This conclusion is further substantiated by the outcome of the fluorescence correlation spectroscopy (FCS) study. Further anal. of data and thermodn. calcns. have revealed that the surface ligands of the CuNCs play an important role in the protein-NCs binding events, and they can alter the mode and thermodn. of the process. Specifically, the data have demonstrated that the binding of BSA with TA-CuNCs and Chitosan-CuNCs follows two types of binding modes; however, the same with Cys-CuNCs goes through only one type of binding mode. CD (CD) measurements have indicated that the basic structure of BSA remains almost unaltered in the presence of CuNCs. The outcome of the present study is expected to encourage and enable better application of NCs in biol. applications.
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Abstract
Figure 1
Figure 1. Scheme of the several reactions in which copper plays a role in wound healing. Reprinted with permission from ref (20). Copyright 2016 Elsevier.
Figure 2
Figure 2. Left: SEM images showing the morphology of substrates with different amount of CuNPs at two magnifications: (a, b) outer eggshell membrane (ESM), (c, d) 0Cu-BG/ESM, (e, f) 2Cu-BG/ESM, and (g, h) 5Cu-BG/ESM. Right: Detection of increased vessel by immunofluorescence of CD31 (green) at day 7. Nuclei are stained with DAPI (blue). Vascularized areas are indicated by pink arrows. Scale bar = 100 μm. Reprinted with permission from ref (67). Copyright 2016 Elsevier.
Figure 3
Figure 4
Figure 4. Upper graphs: Ratio between the weight of swollen hydrogel at time t and the weight of swollen hydrogel at equilibrium state. Lower graphs: Antibacterial activity of the hydrogels against E. coli, C. albicans, and S. aureus (itaconic acid concentration is varied). Reprinted with permission from ref (72). Copyright 2015 Elsevier.
Figure 5
Figure 5. Live–dead staining at laser scanning confocal microscopy are in picture 1, 2, and 3 (red cells = dead, green cells = dead, fibers = red for autofluorescence). SEMs of copper–cotton substrates are in picture 4, 5, and 6. Graph A: Antimicrobial activity against A. baumannii at different times. Graph B: A direct comparison among Cu- and Ag-coated cotton substrates and a commercial silver wound dressing, Acticoat. Graph C: Plot showing about 3-log kill for Cu-cotton samples in the presence of A. baumannii. Reprinted with permission from ref (75). Copyright 2011 John Wiley and Sons.
Figure 6
Figure 6. (A) Steps of healing of infected wounds in mice on days 0, 2, 4, 8, and 14. (B) Wound area closure (%) at different times points. (C) Bacteria from the wound tissues on LB agar plates (a: control; b: hydrogel; c: hydrogel + laser; d: Cu-NP-embedded hydrogel; e: Cu-NP-embedded hydrogel + laser). (D) Log of total bacterial CFU on the LB agar plates. Reprinted with permission from ref (55). Copyright 2013 Royal Society of Chemistry.
Figure 7
Figure 7. Upper panel: Photos and relative survival rates of ESBL E. coli (up) and MRSA E. coli (down). In the graphs The amount of bacteria is reported vs the concentration of NPs. Down panel: TEM images of ESBL E. coli and MRSA for CuS NPs, CuS NDs with and without laser irradiation (2.5 W/cm2, 10 min). Reprinted with permission from ref (91). Copyright 2019 American Chemical Society, with Creative Commons Attribution (CC BY) license.
Figure 8
Figure 8. Cells viability normalized on the control vs concentration (logarithmic) of CuNPs at (a) 4 h and (b) 24 h. Lines and colors refer to different surface ligands on NPs (8-mercaptooctanoic acid (MOA), 12-mercaptododecanoic acid (MDA), and 16-mercaptohexa-decanoic acid (MHA)). Reprinted with permission from ref (103). Copyright 2009 Royal Society of Chemistry.
Figure 9
Figure 9. (A) Copper in the urine of mice at different times post injection. (B) Biodistribution of Cu(I)-GSH and Cu(I) complex (Cu(II)-GSSG). (C) Liver to urine ratios of the two complexes at 24 h. (D) Fluorescence intensity of the complexes (black is Cu(I) complex, red the Cu(II) complex). (E) Time dependence of copper distribution in kidneys and bladder. Reprinted with permission from ref (111). Copyright 2017 The Authors, published open access by MDPI under Creative Commons Attribution (CC BY) license.
Figure 10
Figure 10. Upper panels: Renal clearance and biodistribution studies of GSH-CuS NDs. (A) Absorption spectra of urine samples before and 1 h after the injection. (B) Amount of Cu excreted in urine. (C) Biodistribution of GSH-CuS NDs at 24 h post-injection. D) MR images of GSH-CuS NDs enhanced (from a to j: pre-injection and 30 s, 1 min, 2.5 min, 5.5 min, 10.5 min, 30.5 min, 1 h, 2 h, and 24 h post-injection signal enhancement in heart (B) and bladder (C) caused by GSH-CuS NDs. Reprinted with permission from ref (113). Copyright 2013 Royal Society of Chemistry.
Figure 11
References
This article references 138 other publications.
- 1Luo, G.; Gao, S. Global Health Concerns Stirred by Emerging Viral Infections. J. Med. Virol. 2020, 92 (4), 399– 400, DOI: 10.1002/jmv.256831Global health concerns stirred by emerging viral infectionsLuo, Guangxiang; Gao, Shou-JiangJournal of Medical Virology (2020), 92 (4), 399-400CODEN: JMVIDB; ISSN:0146-6615. (Wiley-Blackwell)A review. The most recent outbreak of viral pneumonia in the city of Wuhan, China, which started in the middle of Dec., 2019 and now is spreading to many places in China as well as to many other countries and regions around the world, serves as an important reminder of our vulnerability to emerging viral infections. Further characterization of the isolated virus in cell culture and animal models will provide valuable information as to the underlying mol. mechanism of viral replication and pathogenesis. More significantly, identification of animal reservoir and intermediate hosts for the 2019-nCoV is crit. for intervention and prevention of the outbreak. It is of paramount importance to develop sensitive and reliable diagnostic methods for rapid detection of viral infection, including immunoassay for quantification of virus-specific antibodies. The ultimate control of emerging viral infections requires discovery and development of effective antiviral drugs and vaccines, which may take months or evenyears. However, it is possible that some of the licensed antiviral drugs for treatment of other viral infections may also have activity against the 2019-nCoV, as previously reported for MERS CoV. More importantly, isolation and cloning of virus-neutralizing antibodies from recovered patients will immediately impact on the treatment and prevention of 2019-CoV infection.
- 2Fisher, R. A.; Gollan, B.; Helaine, S. Persistent Bacterial Infections and Persister Cells. Nat. Rev. Microbiol. 2017, 15, 453– 464, DOI: 10.1038/nrmicro.2017.422Persistent bacterial infections and persister cellsFisher, Robert A.; Gollan, Bridget; Helaine, SophieNature Reviews Microbiology (2017), 15 (8), 453-464CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. Many bacteria can infect and persist inside their hosts for long periods of time. This can be due to immunosuppression of the host, immune evasion by the pathogen and/or ineffective killing by antibiotics. Bacteria can survive antibiotic treatment if they are resistant or tolerant to a drug. Persisters are a subpopulation of transiently antibiotic-tolerant bacterial cells that are often slow-growing or growth-arrested, and are able to resume growth after a lethal stress. The formation of persister cells establishes phenotypic heterogeneity within a bacterial population and has been hypothesized to be important for increasing the chances of successfully adapting to environmental change. The presence of persister cells can result in the recalcitrance and relapse of persistent bacterial infections, and it has been linked to an increase in the risk of the emergence of antibiotic resistance during treatment. If the mechanisms of the formation and regrowth of these antibiotic-tolerant cells were better understood, it could lead to the development of new approaches for the eradication of persistent bacterial infections. In this Review, we discuss recent developments in our understanding of bacterial persisters and their potential implications for the treatment of persistent infections.
- 3Akhavan, O.; Ghaderi, E. Cu and CuO Nanoparticles Immobilized by Silica Thin Films as Antibacterial Materials and Photocatalysts. Surf. Coat. Technol. 2010, 205 (1), 219– 223, DOI: 10.1016/j.surfcoat.2010.06.0363Cu and CuO nanoparticles immobilized by silica thin films as antibacterial materials and photocatalystsAkhavan, O.; Ghaderi, E.Surface and Coatings Technology (2010), 205 (1), 219-223CODEN: SCTEEJ; ISSN:0257-8972. (Elsevier B.V.)CuO nanoparticles with av. diam. of about 20 nm were accumulated on surface of sol-gel silica thin films heat treated at 300 °C in air. Heat treatment of the CuO nanoparticles at 600 °C in a reducing environment resulted in effective redn. of the nanoparticles and penetration of them into the film. While the thin films heat treated at 300 °C exhibited a strong antibacterial activity against Escherichia coli bacteria, the reducing process decreased their antibacterial activity. However, by definition of normalized antibacterial activity (antibacterial activity/surface concn. of coppers) it was found that Cu nanoparticles were more toxic to the bacteria than the CuO nanoparticles (by a factor of ∼ 2.1). Thus, the lower antibacterial activity of the reduced thin films was assigned to diffusion of the initially accumulated copper-based nanoparticles into the film. The CuO nanoparticles also exhibited a slight photocatalytic activity for inactivation of the bacteria (∼ 22% improvement in their antibacterial activity). Instead, the normalized antibacterial activity of the Cu nanoparticles covered by a thin oxide layer highly increased (∼ 63% improvement) in the photocatalytic process. A mechanism was also proposed to describe the better antibacterial activity of the Cu than CuO nanoparticles in dark and under light irradn.
- 4Labruère, R.; Sona, A. J.; Turos, E. Anti-Methicillin-Resistant Staphylococcus aureus Nanoantibiotics. Front. Pharmacol. 2019, 10 (October), 1121, DOI: 10.3389/fphar.2019.011214Anti-methicillin-resistant Staphylococcus aureus nanoantibioticsLabruere, Raphael; Sona, A. J.; Turos, EdwardFrontiers in Pharmacology (2019), 10 (), 1121CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. Nanoparticle-based antibiotic constructs have become a popular area of investigation in the biomedical sciences. Much of this work has pertained to human diseases, largely in the cancer therapy arena. However, considerable research has also been devoted to the nanochem. for controlling infectious diseases. Among these are ones due to bacterial infections, which can cause serious illnesses leading to death. The onset of multi-drug-resistant (MDR) infections such as those caused by the human pathogen Staphylococcus aureus has created a dearth of problems such as surgical complications, persistent infections, and lack of available treatments. In this article, we set out to review the primary literature on the design and development of new nanoparticle materials for the potential treatment of S. aureus infections, and areas that could be further expanded upon to make nanoparticle antibiotics a mainstay in clin. settings.
- 5Merlin, C. Reducing the Consumption of Antibiotics: Would That Be Enough to Slow Down the Dissemination of Resistances in the Downstream Environment?. Front. Microbiol. 2020, 11 (January), 33, DOI: 10.3389/fmicb.2020.000335Reducing the Consumption of Antibiotics: Would That Be Enough to Slow Down the Dissemination of Resistances in the Downstream Environment?Merlin ChristopheFrontiers in microbiology (2020), 11 (), 33 ISSN:1664-302X.There is no expanded citation for this reference.
- 6Zaman, S. B.; Hussain, M. A.; Nye, R.; Mehta, V.; Mamun, K. T.; Hossain, N. A Review on Antibiotic Resistance: Alarm Bells Are Ringing. Cureus 2017, 9 (6), e1403, DOI: 10.7759/cureus.1403There is no corresponding record for this reference.
- 7Chatterjee, A.; Modarai, M.; Naylor, N. R.; Boyd, S. E.; Atun, R.; Barlow, J.; Holmes, A. H.; Johnson, A.; Robotham, J. V. Quantifying Drivers of Antibiotic Resistance in Humans: A Systematic Review. Lancet Infect. Dis. 2018, 18 (12), e368– e378, DOI: 10.1016/S1473-3099(18)30296-27Quantifying drivers of antibiotic resistance in humans: a systematic reviewChatterjee, Anuja; Modarai, Maryam; Naylor, Nichola R.; Boyd, Sara E.; Atun, Rifat; Barlow, James; Holmes, Alison H.; Johnson, Alan; Robotham, Julie V.Lancet Infectious Diseases (2018), 18 (12), e368-e378CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)A review. Mitigating the risks of antibiotic resistance requires a horizon scan linking the quality with the quantity of data reported on drivers of antibiotic resistance in humans, arising from the human, animal, and environmental reservoirs. We did a systematic review using a One Health approach to survey the key drivers of antibiotic resistance in humans. Two sets of reviewers selected 565 studies from a total of 2819 titles and abstrs. identified in Embase, MEDLINE, and Scopus (2005-18), and the European Center for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and WHO (One Health data). Study quality was assessed in accordance with Cochrane recommendations. Previous antibiotic exposure, underlying disease, and invasive procedures were the risk factors with most supporting evidence identified from the 88 risk factors retrieved. The odds ratios of antibiotic resistance were primarily reported to be between 2 and 4 for these risk factors when compared with their resp. controls or baseline risk groups. Food-related transmission from the animal reservoir and water-related transmission from the environmental reservoir were frequently quantified. Uniformly quantifying relationships between risk factors will help researchers to better understand the process by which antibiotic resistance arises in human infections.
- 8Kaufmann, S.; Dorhoi, A.; Hotchkiss, R.; Bartenschlager, R. Host-Directed Therapies for Bacterial and Viral Infections. Nat. Rev. Drug Discovery 2018, 17, 35– 56, DOI: 10.1038/nrd.2017.1628Host-directed therapies for bacterial and viral infectionsKaufmann, Stefan H. E.; Dorhoi, Anca; Hotchkiss, Richard S.; Bartenschlager, RalfNature Reviews Drug Discovery (2018), 17 (1), 35-56CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and addnl. alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathol. Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial. In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with sol. factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory mols.). This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic.
- 9Sánchez-López, E.; Gomes, D.; Esteruelas, G.; Bonilla, L.; Lopez-Machado, A. L.; Galindo, R.; Cano, A.; Espina, M.; Ettcheto, M.; Camins, A.; Silva, A. M.; Durazzo, A.; Santini, A.; Garcia, M. L.; Souto, E. B. Metal-Based Nanoparticles as Antimicrobial Agents: An Overview. Nanomaterials 2020, 10, 292, DOI: 10.3390/nano100202929Metal-based nanoparticles as antimicrobial agents: an overviewSanchez-Lopez, Elena; Gomes, Daniela; Esteruelas, Gerard; Bonilla, Lorena; Lopez-Machado, Ana Laura; Galindo, Ruth; Cano, Amanda; Espina, Marta; Ettcheto, Miren; Camins, Antoni; Silva, Amelia M.; Durazzo, Alessandra; Santini, Antonello; Garcia, Maria L.; Souto, Eliana B.Nanomaterials (2020), 10 (2), 292CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addn. to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-pos. and Gram-neg. bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their prodn. methods, physicochem. characterization, and pharmacokinetics together with the toxicol. risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-neg. bacteria has been highlighted.
- 10Lemire, J. A.; Harrison, J. J.; Turner, R. J. Antimicrobial Activity of Metals: Mechanisms, Molecular Targets and Applications. Nat. Rev. Microbiol. 2013, 11, 371– 384, DOI: 10.1038/nrmicro302810Antimicrobial activity of metals: mechanisms, molecular targets and applicationsLemire, Joseph A.; Harrison, Joe J.; Turner, Raymond J.Nature Reviews Microbiology (2013), 11 (6), 371-384CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. Metals have been used as antimicrobial agents since antiquity, but throughout most of history their modes of action have remained unclear. Recent studies indicate that different metals cause discrete and distinct types of injuries to microbial cells as a result of oxidative stress, protein dysfunction or membrane damage. Here, the authors describe the chem. and toxicol. principles that underlie the antimicrobial activity of metals and discuss the preferences of metal atoms for specific microbial targets. Interdisciplinary research is advancing not only the authors' understanding of metal toxicity but also the design of metal-based compds. for use as antimicrobial agents and alternatives to antibiotics.
- 11Wang, W.; Li, B.; Yang, H.; Lin, Z.; Chen, L.; Li, Z.; Ge, J.; Zhang, T.; Xia, H.; Li, L.; Lu, Y. Efficient Elimination of Multidrug-Resistant Bacteria Using Copper Sulfide Nanozymes Anchored to Graphene Oxide Nanosheets. Nano Res. 2020, 13 (8), 2156– 2164, DOI: 10.1007/s12274-020-2824-711Efficient elimination of multidrug-resistant bacteria using copper sulfide nanozymes anchored to graphene oxide nanosheetsWang, Wanshun; Li, Binglin; Yang, Huili; Lin, Zefeng; Chen, Lingling; Li, Zhan; Ge, Jiayuan; Zhang, Tao; Xia, Hong; Li, Lihua; Lu, YaoNano Research (2020), 13 (8), 2156-2164CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)Abstr.: Antibacterial nanomaterials have attracted growing interest for bacterial infection therapy. However, most nanomaterials eliminate bacteria either phys. or chem., which hampers their efficacy when dealing with multidrug-resistant bacteria. To overcome this, we integrated copper sulfide (CuS) nanoparticles with active graphene oxide nanosheets (GO NSs) to synthesize a superior nanocomposite (CuS/GO NC) that acts both phys. and chem. on the bacteria. CuS/GO NC was produced using a facile hydrothermal method, whereby the CuS nanoparticles grew and were uniformly dispersed on the GO NSs in situ. We found that the CuS/GO NC possesses a unique needle-like morphol. that phys. damages the bacterial cell membrane. CuS/GO NC also exhibits high oxidase- and peroxidase-like activity, ensuring efficient generation of the reactive oxygen species •OH from H2O2, which kills bacteria chem. These features endow the CuS/GO NC with excellent antibacterial capabilities to kill multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) with only a single dose. Addnl., it was found that the CuS/GO NC accelerated the healing of infected wounds in vivo owing to its good biocompatibility as well as facilitation of cell migration and collagen secretion. This study provides a new strategy to combine the phys. and chem. antibacterial modes of nanomaterials to develop more effective therapies to combat multidrug-resistant bacterial infections. [graphic not available: see fulltext].
- 12Lemire, J. A.; Harrison, J. J.; Turner, R. J. Antimicrobial Activity of Metals: Mechanisms, Molecular Targets and Applications. Nat. Rev. Microbiol. 2013, 11, 371– 384, DOI: 10.1038/nrmicro302812Antimicrobial activity of metals: mechanisms, molecular targets and applicationsLemire, Joseph A.; Harrison, Joe J.; Turner, Raymond J.Nature Reviews Microbiology (2013), 11 (6), 371-384CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. Metals have been used as antimicrobial agents since antiquity, but throughout most of history their modes of action have remained unclear. Recent studies indicate that different metals cause discrete and distinct types of injuries to microbial cells as a result of oxidative stress, protein dysfunction or membrane damage. Here, the authors describe the chem. and toxicol. principles that underlie the antimicrobial activity of metals and discuss the preferences of metal atoms for specific microbial targets. Interdisciplinary research is advancing not only the authors' understanding of metal toxicity but also the design of metal-based compds. for use as antimicrobial agents and alternatives to antibiotics.
- 13Roy, K.; Sarkar, C. K.; Ghosh, C. K. Antibacterial Mechanism of Biogenic Copper Nanoparticles Synthesized Using Heliconia Psittacorum Leaf Extract. Nanotechnol. Rev. 2016, 5 (6), 529– 536, DOI: 10.1515/ntrev-2016-004013Antibacterial mechanism of biogenic copper nanoparticles synthesized using Heliconia psittacorum leaf extractRoy, Kaushik; Sarkar, Chandan K.; Ghosh, Chandan K.Nanotechnology Reviews (2016), 5 (6), 529-536CODEN: NRAEE8; ISSN:2191-9097. (Walter de Gruyter GmbH)Here, we report on the novel green synthesis of metallic copper nanoparticles from copper sulfate soln. by using the leaf ext. of Heliconia psittacorum. The stability and gradual formation of copper nanoparticles during interaction with the ext. were investigated using UV-visible spectroscopy. The pattern of X-ray diffraction revealed the crystallinity and different phases of the nanoparticles. High-resoln. transmission electron microscopy was done to obtain information about the morphol. and microstructure of the green nanoparticles. The IR spectra detected org. bioactive mols. assocd. with capping and stabilization of the particle surface. The antibacterial properties of these bioengineered Cu nanoparticles were tested toward a Gram-pos. bacteria - Staphylococcus aureus - and two strains of Gram-neg. bacteria - Escherichia coli and Pseudomonas putida. The antibacterial study showed that these biogenic copper nanoparticles have potent bactericidal property toward the examd. bacterial species.
- 14Ramteke, L.; Gawali, P.; Jadhav, B. L.; Chopade, B. A. Comparative Study on Antibacterial Activity of Metal Ions, Monometallic and Alloy Noble Metal Nanoparticles against Nosocomial Pathogens. Bionanoscience 2020, 10, 1018, DOI: 10.1007/s12668-020-00771-9There is no corresponding record for this reference.
- 15Poggio, C.; Colombo, M.; Arciola, C. R.; Greggi, T.; Scribante, A.; Dagna, A. Copper-Alloy Surfaces and Cleaning Regimens against the Spread of SARS-CoV-2 in Dentistry and Orthopedics. From Fomites to Anti-Infective Nanocoatings. Materials 2020, 13 (15), 3244, DOI: 10.3390/ma1315324415Copper-alloy surfaces and cleaning regimens against the spread of SARS-CoV-2 in dentistry and orthopedics. from fomites to anti-infective nanocoatingsPoggio, Claudio; Colombo, Marco; Arciola, Carla Renata; Greggi, Tiziana; Scribante, Andrea; Dagna, AlbertoMaterials (2020), 13 (15), 3244CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)The latest diffusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease (COVID-19), has involved the whole world population. Even if huge efforts to control the pandemic have been done, the viral spread is still continuing. COVID-19 is reported as a zoonosis jumped from bats and pangolins to humans. After infection in humans, SARS-CoV-2 is found in the nasopharyngeal and salivary secretions. The virus has also been detected in the blood plasma of infected patients. The viral spread occurs through droplets exhaled from the nose and mouth of the infected people when they breath or talk, or through droplets propelled as a dense cloud by chough or sneeze. The virus can also be delivered as an aerosol from blood plasma, through surgical procedures. Following these ways, the virus can disperse in the air, then reaching and settling on the exposed surfaces. How long the virus will survive on a surface depends on the material the surface is made from. Infection via high-touch surfaces should be prevented. Copper alloy coatings, combined with efficient hygienic/disinfectant procedures and careful surgical practice, could be helpful to health protection in dental practice and can also be adopted in orthopedic traumatol.
- 16Gawande, M. B.; Goswami, A.; Felpin, F. O.-X.; Asefa, T.; Huang, X.; Silva, R.; Zou, X.; Zboril, R.; Varma, R. S. Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis. Chem. Rev. 2016, 116, 3722– 3811, DOI: 10.1021/acs.chemrev.5b0048216Cu and Cu-Based Nanoparticles: Synthesis and Applications in CatalysisGawande, Manoj B.; Goswami, Anandarup; Felpin, Francois-Xavier; Asefa, Tewodros; Huang, Xiaoxi; Silva, Rafael; Zou, Xiaoxin; Zboril, Radek; Varma, Rajender S.Chemical Reviews (Washington, DC, United States) (2016), 116 (6), 3722-3811CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)The applications of copper (Cu) and Cu-based nanoparticles, which are based on the earth-abundant and inexpensive copper metal, have generated a great deal of interest in recent years, esp. in the field of catalysis. The possible modification of the chem. and phys. properties of these nanoparticles using different synthetic strategies and conditions and/or via postsynthetic chem. treatments has been largely responsible for the rapid growth of interest in these nanomaterials and their applications in catalysis. In addn., the design and development of novel support and/or multimetallic systems (e.g., alloys, etc.) has also made significant contributions to the field. In this comprehensive review, we report different synthetic approaches to Cu and Cu-based nanoparticles (metallic copper, copper oxides, and hybrid copper nanostructures) and copper nanoparticles immobilized into or supported on various support materials (SiO2, magnetic support materials, etc.), along with their applications in catalysis. The synthesis part discusses numerous preparative protocols for Cu and Cu-based nanoparticles, whereas the application sections describe their utility as catalysts, including electrocatalysis, photocatalysis, and gas-phase catalysis. We believe this crit. appraisal will provide necessary background information to further advance the applications of Cu-based nanostructured materials in catalysis.
- 17Nikolova, M. P.; Chavali, M. S. Metal Oxide Nanoparticles as Biomedical Materials. Biomimetics 2020, 5 (2), 27, DOI: 10.3390/biomimetics502002717Metal oxide nanoparticles as biomedical materialsNikolova, Maria P.; Chavali, Murthy S.Biomimetics (2020), 5 (2), 27CODEN: BIOMJE; ISSN:2313-7673. (MDPI AG)The development of new nanomaterials with high biomedical performance and low toxicity is essential to obtain more efficient therapy and precise diagnostic tools and devices. Recently, scientists often face issues of balancing between pos. therapeutic effects of metal oxide nanoparticles and their toxic side effects. In this review, considering metal oxide nanoparticles as important technol. and biomedical materials, the authors provide a comprehensive review of researches on metal oxide nanoparticles, their nanoscale physicochem. properties, defining specific applications in the various fields of nanomedicine. Authors discuss the recent development of metal oxide nanoparticles that were employed as biomedical materials in tissue therapy, immunotherapy, diagnosis, dentistry, regenerative medicine, wound healing and biosensing platforms. Besides, their antimicrobial, antifungal, antiviral properties along with biotoxicol. were debated in detail. The significant breakthroughs in the field of nanobiomedicine have emerged in areas and nos. predicting tremendous application potential and enormous market value for metal oxide nanoparticles.
- 18Sánchez-López, E.; Gomes, D.; Esteruelas, G.; Bonilla, L.; Lopez-Machado, A. L.; Galindo, R.; Cano, A.; Espina, M.; Ettcheto, M.; Camins, A.; Silva, A. M.; Durazzo, A.; Santini, A.; Garcia, M. L.; Souto, E. B. Metal-Based Nanoparticles as Antimicrobial Agents: An Overview. Nanomaterials 2020, 10 (2), 292, DOI: 10.3390/nano1002029218Metal-based nanoparticles as antimicrobial agents: an overviewSanchez-Lopez, Elena; Gomes, Daniela; Esteruelas, Gerard; Bonilla, Lorena; Lopez-Machado, Ana Laura; Galindo, Ruth; Cano, Amanda; Espina, Marta; Ettcheto, Miren; Camins, Antoni; Silva, Amelia M.; Durazzo, Alessandra; Santini, Antonello; Garcia, Maria L.; Souto, Eliana B.Nanomaterials (2020), 10 (2), 292CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addn. to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-pos. and Gram-neg. bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their prodn. methods, physicochem. characterization, and pharmacokinetics together with the toxicol. risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-neg. bacteria has been highlighted.
- 19Broglie, J. J.; Alston, B.; Yang, C.; Ma, L.; Adcock, A. F.; Chen, W.; Yang, L. Antiviral Activity of Gold/Copper Sulfide Core/Shell Nanoparticles against Human Norovirus Virus-Like Particles. PLoS One 2015, 10 (10), e0141050 DOI: 10.1371/journal.pone.014105019Antiviral activity of gold/copper sulfide core/shell nanoparticles against human norovirus virus-like particlesBroglie, Jessica Jenkins; Alston, Brittny; Yang, Chang; Ma, Lun; Adcock, Audrey F.; Chen, Wei; Yang, LijuPLoS One (2015), 10 (10), e0141050/1-e0141050/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Human norovirus is a leading cause of acute gastroenteritis worldwide in a plethora of residential and com. settings, including restaurants, schools, and hospitals. Methods for easily detecting the virus and for treating and preventing infection are crit. to stopping norovirus outbreaks, and inactivation via nanoparticles (NPs) is a more universal and attractive alternative to other phys. and chem. approaches. Using norovirus GI.1 (Norwalk) virus-like particles (VLPs) as a model viral system, this study characterized the antiviral activity of Au/CuS core/shell nanoparticles (NPs) against GI.1 VLPs for the rapid inactivation of HuNoV. Inactivation of VLPs (GI.1) by Au/CuS NPs evaluated using an absorbancebased ELISA indicated that treatment with 0.083 μM NPs for 10 min inactivated ∼50% VLPs in a 0.37 μg/mL VLP soln. and 0.83 μM NPs for 10 min completely inactivated the VLPs. Increasing nanoparticle concn. and/or VLP-NP contact time significantly increased the virucidal efficacy of Au/CuS NPs. Changes to the VLP particle morphol., size, and capsid protein were characterized using dynamic light scattering, transmission electron microscopy, and Western blot anal. The strategy reported here provides the first reported proof-of-concept Au/CuS NPs-based virucide for rapidly inactivating human norovirus.
- 20Kornblatt, A. P.; Nicoletti, V. G.; Travaglia, A. The Neglected Role of Copper Ions in Wound Healing. J. Inorg. Biochem. 2016, 161, 1– 8, DOI: 10.1016/j.jinorgbio.2016.02.01220The neglected role of copper ions in wound healingKornblatt, Allison Paige; Nicoletti, Vincenzo Giuseppe; Travaglia, AlessioJournal of Inorganic Biochemistry (2016), 161 (), 1-8CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)A review. Wound healing is a complex biol. process that aims to repair damaged tissue. Even though many biol. and biochem. mechanisms assocd. with the steps of physiol. wound healing are known, there is still significant morbidity and mortality due to dysregulation of physiol. mechanisms. It might be useful to revise the activity of old players and their links with new, often neglected, mol. entities. This review revises new findings supporting the hypothesis that copper ions regulate the activity and/or the expression of proteins crucially involved in the wound repair process. A better understanding of these interactions might suggest potential new targets for therapeutic intervention on scars or non-healing wounds.
- 21Yamada, M.; Foote, M.; Prow, T. W. Therapeutic Gold, Silver, and Platinum Nanoparticles. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2015, 7 (3), 428– 445, DOI: 10.1002/wnan.132221Therapeutic gold, silver, and platinum nanoparticlesYamada, Miko; Foote, Matthew; Prow, Tarl W.Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology (2015), 7 (3), 428-445CODEN: WIRNBH; ISSN:1939-0041. (Wiley-Blackwell)A review. There are an abundance of nanoparticle technologies being developed for use as part of therapeutic strategies. This review focuses on a narrow class of metal nanoparticles that have therapeutic potential that is a consequence of elemental compn. and size. The most widely known of these are gold nanoshells that have been developed over the last two decades for photothermal ablation in superficial cancers. The therapeutic effect is the outcome of the thickness and diam. of the gold shell that enables fine tuning of the plasmon resonance. When these metal nanoparticles are exposed to the relevant wavelength of light, their temp. rapidly increases. This in turn induces a localized photothermal ablation that kills the surrounding tumor tissue. Similarly, gold nanoparticles have been developed to enhance radiotherapy. The high-Z nature of gold dramatically increases the photoelec. cross-section. Thus, the photoelec. effects are significantly increased. The outcome of these interactions is enhanced tumor killing with lower doses of radiation, all while sparing tissue without gold nanoparticles. Silver nanoparticles have been used for their wound healing properties in addn. to enhancing the tumor-killing effects of anticancer drugs. Finally, platinum nanoparticles are thought to serve as a reservoir for platinum ions that can induce DNA damage in cancer cells. The future is bright with the path to clin. trials is largely cleared for some of the less complex therapeutic metal nanoparticle systems.
- 22Rubilar, O.; Rai, M.; Tortella, G.; Diez, M. C.; Seabra, A. B.; Durán, N. Biogenic Nanoparticles: Copper, Copper Oxides, Copper Sulphides, Complex Copper Nanostructures and Their Applications. Biotechnol. Lett. 2013, 35 (9), 1365– 1375, DOI: 10.1007/s10529-013-1239-x22Biogenic nanoparticles: copper, copper oxides, copper sulphides, complex copper nanostructures and their applicationsRubilar, Olga; Rai, Mahendra; Tortella, Gonzalo; Diez, Maria Cristina; Seabra, Amedea B.; Duran, NelsonBiotechnology Letters (2013), 35 (9), 1365-1375CODEN: BILED3; ISSN:0141-5492. (Springer)A review. Copper nanoparticles have been the focus of intensive study due to their potential applications in diverse fields including biomedicine, electronics, and optics. Copper-based nanostructured materials have been used in conductive films, lubrification, nanofluids, catalysis, and also as potent antimicrobial agent. The biogenic synthesis of metallic nanostructured nanoparticles is considered to be a green and eco-friendly technol. since neither harmful chems. nor high temps. are involved in the process. The present review discusses the synthesis of copper nanostructured nanoparticles by bacteria, fungi, and plant exts., showing that biogenic synthesis is an economically feasible, simple and non-polluting process. Applications for biogenic copper nanoparticles are also discussed.
- 23Zhou, Y.; Wei, F.; Zhang, W.; Guo, Z.; Zhang, L. Copper Bioaccumulation and Biokinetic Modeling in Marine Herbivorous Fish Siganus Oramin. Aquat. Toxicol. 2018, 196, 61– 69, DOI: 10.1016/j.aquatox.2018.01.00923Copper bioaccumulation and biokinetic modeling in marine herbivorous fish Siganus oraminZhou, Yanyan; Wei, Fangsan; Zhang, Wei; Guo, Zhiqiang; Zhang, LiAquatic Toxicology (2018), 196 (), 61-69CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)Marine herbivorous fish directly consume macroalgae, which commonly accumulate high levels of trace metals in polluted areas. We proposed that herbivorous fish could be better candidates for biomonitoring marine metal pollution than carnivorous fish. To date, the trophic transfer of Cu from macroalgae to marine herbivorous fish is unclear. In this study, the kinetics of Cu bioaccumulation in a widespread marine herbivorous fish, Siganus oramin, were investigated, and biokinetic modeling was applied to est. the Cu levels in the fish sampled from different sites and seasons. The results showed that Cu accumulation in the fish was linearly correlated to the dietary Cu levels in the different prey species, which were proportional to the waterborne Cu concns. The Cu found in the subcellular trophically available metal fraction (TAM) in the prey contributed the largest proportion of accumulated Cu in S. oramin. The dietary assimilation efficiencies (AEs) of Cu were 15.56 ± 1.76%, 13.42 ± 2.86%, and 21.36 ± 1.47% for Ulva lactuca, Gracilaria lemaneiformis and Gracilaria gigas, resp. The calcd. waterborne uptake rate const. (ku) of Cu was 0.023 ± 0.011 L g-1 d-1, and the efflux rate const. (ke) was 0.055 ± 0.021 d-1. Dietary Cu accounted for 60%-75% of the body Cu in S. oramin, suggesting that dietary uptake could be the primary route for Cu bioaccumulation in herbivorous fish. The biokinetic model demonstrated that the Cu concns. in the water and fish presented a pos. linear relationship, which was in line with our field investigation along the coastal areas of South China. Therefore, we suggested that S. oramin could be used as a biomonitoring organism for Cu pollution in the marine environment. However, the heterogeneities between the predicted levels and the measured levels of Cu implied that seasonal changes should be taken into account to improve the accuracy of the model.
- 24Liu, Y.; Gao, Y.; Zhang, L.; Wang, T.; Wang, J.; Jiao, F.; Li, W.; Liu, Y.; Li, Y.; Li, B.; Chai, Z.; Wu, G.; Chen, C. Potential Health Impact on Mice after Nasal Instillation of Nano-Sized Copper Particles and Their Translocation in Mice. J. Nanosci. Nanotechnol. 2009, 9 (11), 6335– 6343, DOI: 10.1166/jnn.2009.132024Potential health impact on mice after nasal instillation of nano-sized copper particles and their translocation in miceLiu, Yang; Gao, Yuxi; Zhang, Lili; Wang, Tiancheng; Wang, Jiangxue; Jiao, Fang; Li, Wei; Liu, Ying; Li, Yufeng; Li, Bai; Chai, Zhifang; Wu, Gang; Chen, ChunyingJournal of Nanoscience and Nanotechnology (2009), 9 (11), 6335-6343CODEN: JNNOAR; ISSN:1533-4880. (American Scientific Publishers)The purpose of this study is to evaluate the overall toxicity of nasal instilled nanoscale copper particles (23.5 nm) in mice. Pathol. examn., target organs identification, and blood biochem. assay of exptl. mice were carried out in comparison with micro-sized copper particles (17 μm). However, only in the high-dose group of copper nanoparticles (40 mg/kg body wt. instilled for three times in one week), the body wt. of mice were retarded and significant pathol. changes were obsd. There were hydropic degeneration around the central vein and the spotty necrosis of hepatocytes in the liver and swelling in the renal glomerulus, while, severe lesion assocd. with the decreased no. of olfactory cells and the dilapidated laminated structure were also obsd. in the olfactory bulb. The serum biochem. assay also indicated the sign of renal and hepatic lesion. However, there were no obvious pathol. and physiol. damages in the mice after instilling different-sized copper nanoparticles with low dose of 1 mg/kg body wt. The retention and distribution of copper in various tissues show that the liver, kidneys and olfactory bulb are the main accumulated tissues for copper particles, which were detd. by high sensitive element-specific technique of ICP-MS. The copper contents of the liver, kidneys and the olfactory bulb increase significantly at the group of 40 mg/kg compared to the control group, which is in agreement with the histol. changes. Therefore, the data indicate that nasal inhaled copper particles at very high dosage can translocate to other organs and tissues and further induce certain lesions. The present results are helpful to get better understanding of the risk assessment and evaluation for copper nanoparticles.
- 25Patel, R.; Aschner, M. Commonalities between Copper Neurotoxicity and Alzheimer’s Disease. Toxics 2021, 9 (1), 4, DOI: 10.3390/toxics9010004There is no corresponding record for this reference.
- 26Karlsson, H. L.; Cronholm, P.; Gustafsson, J.; Möller, L. Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon Nanotubes. Chem. Res. Toxicol. 2008, 21 (9), 1726– 1732, DOI: 10.1021/tx800064j26Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon NanotubesKarlsson, Hanna L.; Cronholm, Pontus; Gustafsson, Johanna; Moeller, LennartChemical Research in Toxicology (2008), 21 (9), 1726-1732CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Since the manuf. and use of nanoparticles are increasing, humans are more likely to be exposed occupationally or via consumer products and the environment. However, so far toxicity data for most manufd. nanoparticles are limited. The aim of this study was to investigate and compare different nanoparticles and nanotubes regarding cytotoxicity and ability to cause DNA damage and oxidative stress. The study was focused on different metal oxide particles (CuO, TiO2, ZnO, CuZnFe2O4, Fe3O4, Fe2O3), and the toxicity was compared to that of carbon nanoparticles and multiwalled carbon nanotubes (MWCNT). The human lung epithelial cell line A549 was exposed to the particles, and cytotoxicity was analyzed using trypan blue staining. DNA damage and oxidative lesions were detd. using the comet assay, and intracellular prodn. of reactive oxygen species (ROS) was measured using the oxidn.-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate (DCFH-DA). The results showed that there was a high variation among different nanoparticles concerning their ability to cause toxic effects. CuO nanoparticles were most potent regarding cytotoxicity and DNA damage. The toxicity was likely not explained by Cu ions released to the cell medium. These particles also caused oxidative lesions and were the only particles that induced an almost significant increase (p = 0.058) in intracellular ROS. ZnO showed effects on cell viability as well as DNA damage, whereas the TiO2 particles (a mix of rutile and anatase) only caused DNA damage. For iron oxide particles (Fe3O4, Fe2O3), no or low toxicity was obsd., but CuZnFe2O4 particles were rather potent in inducing DNA lesions. Finally, the carbon nanotubes showed cytotoxic effects and caused DNA damage in the lowest dose tested. The effects were not explained by sol. metal impurities. In conclusion, this study highlights the in vitro toxicity of CuO nanoparticles.
- 27Bahadar, H.; Maqbool, F.; Niaz, K.; Abdollahi, M. Toxicity of Nanoparticles and an Overview of Current Experimental Models. Iranian Biomedical Journal 2016, 20 (1), 1– 11, DOI: 10.7508/ibj.2016.01.00128Toxicity of Nanoparticles and an Overview of Current Experimental ModelsBahadar Haji; Maqbool Faheem; Niaz Kamal; Abdollahi Mohammad; Abdollahi Mohammad; Abdollahi MohammadIranian biomedical journal (2016), 20 (1), 1-11 ISSN:.Nanotechnology is a rapidly growing field having potential applications in many areas. Nanoparticles (NPs) have been studied for cell toxicity, immunotoxicity, and genotoxicity. Tetrazolium-based assays such as MTT, MTS, and WST-1 are used to determine cell viability. Cell inflammatory response induced by NPs is checked by measuring inflammatory biomarkers, such as IL-8, IL-6, and tumor necrosis factor, using ELISA. Lactate dehydrogenase (LDH) assay is used for cell membrane integrity. Different types of cell cultures, including cancer cell lines have been employed as in vitro toxicity models. It has been generally agreed that NPs interfere with either assay materials or with detection systems. So far, toxicity data generated by employing such models are conflicting and inconsistent. Therefore, on the basis of available experimental models, it may be difficult to judge and list some of the more valuable NPs as more toxic to biological systems and vice versa. Considering the potential applications of NPs in many fields and the growing apprehensions of FDA about the toxic potential of nanoproducts, it is the need of the hour to look for new internationally agreed free of bias toxicological models by focusing more on in vivo studies.
- 28Studer, A. M.; Limbach, L. K.; Van Duc, L.; Krumeich, F.; Athanassiou, E. K.; Gerber, L. C.; Moch, H.; Stark, W. J. Nanoparticle Cytotoxicity Depends on Intracellular Solubility: Comparison of Stabilized Copper Metal and Degradable Copper Oxide Nanoparticles. Toxicol. Lett. 2010, 197 (3), 169– 174, DOI: 10.1016/j.toxlet.2010.05.01229Nanoparticle cytotoxicity depends on intracellular solubility: Comparison of stabilized copper metal and degradable copper oxide nanoparticlesStuder, Andreas M.; Limbach, Ludwig K.; Duc, Luu Van; Krumeich, Frank; Athanassiou, Evagelos K.; Gerber, Lukas C.; Moch, Holger; Stark, Wendelin J.Toxicology Letters (2010), 197 (3), 169-174CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Metal nanoparticles have distinctly different chem. and phys. properties than currently investigated oxides. Since pure metallic nanoparticles are igniting at air, carbon stabilized copper nanoparticles were used as representative material for this class. Using copper as a representative example, we compare the cytotoxicity of copper metal nanoparticles stabilized by a carbon layer to copper oxide nanoparticles using two different cell lines. Keeping the copper exposure dose const., the two forms of copper showed a distinctly different response. While copper oxide had already been reported to be highly cytotoxic, carbon-coated copper nanoparticles were much less cytotoxic and more tolerated. Measuring the two material's intra- and extracellular soly. in model buffers explained this difference on the basis of altered copper release when supplying copper metal or the corresponding oxide particles to the cells. Control expts. using pure carbon nanoparticles were used to exclude significant surface effects. Ref. expts. with ionic copper solns. confirmed a similar response of cultures if exposed to copper oxide nanoparticles or ionic copper. These observations are in line with a Trojan horse-type mechanism and illustrate the dominating influence of physico-chem. parameters on the cytotoxicity of a given metal.
- 29Applerot, G.; Lellouche, J.; Lipovsky, A.; Nitzan, Y.; Lubart, R.; Gedanken, A.; Banin, E. Understanding the Antibacterial Mechanism of CuO Nanoparticles: Revealing the Route of Induced Oxidative Stress. Small 2012, 8 (21), 3326– 3337, DOI: 10.1002/smll.20120077230Understanding the antibacterial mechanism of CuO nanoparticles: revealing the route of induced oxidative stressApplerot, Guy; Lellouche, Jonathan; Lipovsky, Anat; Nitzan, Yeshayahu; Lubart, Rachel; Gedanken, Aharon; Banin, EhudSmall (2012), 8 (21), 3326-3337CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)To date, there is still a lack of definite knowledge regarding the interaction of CuO nanoparticles with bacteria and the possible permeation of the nanoparticles into bacterial cells. This study was aimed at shedding light on the size-dependent (from the microscale down to the small nanoscale) antibacterial activity of CuO. The potent antibacterial activity of CuO nanoparticles was found to be due to ROS generation by the nanoparticles attached to the bacterial cells, which in turn provoked an enhancement of the intracellular oxidative stress. This paradigm was confirmed by several assays such as lipid peroxidn. and reporter strains of oxidative stress. Furthermore, electron microscopy indicated that the small nanoparticles of CuO penetrated the cells. Thus, the results reported herein may reconcile conflicting concepts in the literature concerning the antibacterial mechanism of CuO nanoparticles, as well as highlight the potential for developing sustainable CuO nanoparticles-based devices for inhibiting bacterial infections.
- 30Karlsson, H. L.; Cronholm, P.; Hedberg, Y.; Tornberg, M.; De Battice, L.; Svedhem, S.; Wallinder, I. O. Cell Membrane Damage and Protein Interaction Induced by Copper Containing Nanoparticles-Importance of the Metal Release Process. Toxicology 2013, 313 (1), 59– 69, DOI: 10.1016/j.tox.2013.07.01231Cell membrane damage and protein interaction induced by copper containing nanoparticles-Importance of the metal release processKarlsson, Hanna L.; Cronholm, Pontus; Hedberg, Yolanda; Tornberg, Malin; De Battice, Laura; Svedhem, Sofia; Wallinder, Inger OdnevallToxicology (2013), 313 (1), 59-69CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)Cu-contg. nanoparticles are used in various applications in order to e.g. achieve antimicrobial activities and to increase the cond. of fluids and polymers. Several studies have reported on toxic effects of such particles but the mechanisms are not completely clear. The aim of this study was to investigate the interactions between cell membranes and well-characterized nanoparticles of CuO, Cu metal, a binary Cu-Zn alloy and micron-sized Cu metal particles. This was conducted via in vitro investigations of the effects of the nanoparticles on (i) cell membrane damage on lung epithelial cells (A549), (ii) membrane rupture of red blood cells (hemolysis), complemented by (iii) nanoparticle interaction studies with a model lipid membrane using quartz crystal microbalance with dissipation monitoring (QCM-D). The results revealed that nanoparticles of the Cu metal and the Cu-Zn alloy were both highly membrane damaging and caused a rapid (within 1 h) increase in membrane damage at a particle mass dose of 20 μg/mL, whereas the CuO nanoparticles and the micron-sized Cu metal particles showed no such effect. At similar nanoparticle surface area doses, the nano and micron-sized Cu particles showed more similar effects. The commonly used LDH (lactate dehydrogenase) assay for anal. of membrane damage was found impossible to use due to nanoparticle-assay interactions. None of the particles induced any hemolytic effects on red blood cells when investigated up to high particle concns. (1 mg/mL). However, both Cu and Cu-Zn nanoparticles caused Hb aggregation/pptn., a process that would conceal a possible hemolytic effect. Studies on interactions between the nanoparticles and a model membrane using QCM-D indicated a small difference between the investigated particles. Results of this study suggest that the obsd. membrane damage is caused by the metal release process at the cell membrane surface and highlight differences in reactivity between metallic nanoparticles of Cu and Cu-Zn and nanoparticles of CuO.
- 31Wang, Z.; Li, N.; Zhao, J.; White, J. C.; Qu, P.; Xing, B. CuO Nanoparticle Interaction with Human Epithelial Cells: Cellular Uptake, Location, Export, and Genotoxicity. Chem. Res. Toxicol. 2012, 25 (7), 1512– 1521, DOI: 10.1021/tx300209332CuO Nanoparticle Interaction with Human Epithelial Cells: Cellular Uptake, Location, Export, and GenotoxicityWang, Zhenyu; Li, Na; Zhao, Jian; White, Jason C.; Qu, Pei; Xing, BaoshanChemical Research in Toxicology (2012), 25 (7), 1512-1521CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The toxicity of CuO nanoparticles (NPs) to human lung epithelial (A549) cells was investigated in this study. CuO NPs (10-100 mg/L) had significant toxicity to A549 cells, whereas CuO bulk particles (BPs) showed much lower toxicity (24 h IC50, 58 and 15 mg/L for CuO BPs and NPs, resp.). Transmission electron microscopic anal. demonstrated CuO NP entry into A549 cells and organelles, including lysosomes, mitochondria, and nucleus. Endocytosis was the primary pathway of CuO NPs uptake. CuO NPs (15 mg/L) induced mitochondrial depolarization, possibly mediated by reactive oxygen species (ROS) generation. Intracellular CuO NPs 1st generate ROS, which subsequently induces the expression of p38 and p53 and ultimately causes DNA damage (Comet assay). We confirm for the 1st time that the primary cytotoxic response is oxidative stress rather than DNA damage. A fraction of the CuO NPs was exported to the extracellular environment. In this study, centrifugal ultrafiltration tubes were successfully employed to det. the dissolved Cu2+ from CuO NPs in the cell medium. Dissolved Cu2+ ions contributed less than half of the total toxicity caused by CuO NPs, including ROS generation and DNA damage. This study provided useful data for understanding transport and toxicity of metal oxide NPs in human cells.
- 32Vanwinkle, B. A.; De Mesy Bentley, K. L.; Malecki, J. M.; Gunter, K. K.; Evans, I. M.; Elder, A.; Finkelstein, J. N.; Oberdörster, G.; Gunter, T. E. Nanoparticle (NP) Uptake by Type i Alveolar Epithelial Cells and Their Oxidant Stress Response. Nanotoxicology 2009, 3 (4), 307– 318, DOI: 10.3109/1743539090312194933Nanoparticle (NP) uptake by type I alveolar epithelial cells and their oxidant stress responseVanwinkle, Beth A.; de Mesy Bentley, Karen L.; Malecki, Jonathan M.; Gunter, Karlene K.; Evans, Irene M.; Elder, Alison; Finkelstein, Jacob N.; Oberdorster, Gunter; Gunter, Thomas E.Nanotoxicology (2009), 3 (4), 307-318CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)Mammalian cells take up nanoparticles (NPs) and some NPs increase ROS. We used imaging and measure ROS in parallel to evaluate NP-cell interactions with type I-like alveolar epithelial cells exposed to NPs at 1.2 μg/cm2. Titanium dioxide (TiO2), gold (Au), silver (Ag), and manganese (Mn) were internalized by R3-1 cells; copper (Cu) NPs were obsd. at the cell surface only. TiO2 and Au did not increase cell death but Mn and Cu did, with surviving cells recovering after initial Cu exposure. Ag NPs caused 80% of R3-1 cells to lift off the slides within 1 h. Amplex Red was used to report H2O2 prodn. after exposure to 0.4 μg/cm2 TiO2, Au, Cu, Mn and Ag. TiO2, Au, and Ag caused no significant increase in H2O2 while Cu and Mn increased H2O2. NPs that give up electrons, increase ROS prodn. and cause cell death in R3-1 cells.
- 33Cronholm, P.; Midander, K.; Karlsson, H. L.; Elihn, K.; Wallinder, I. O.; Möller, L. Effect of Sonication and Serum Proteins on Copper Release from Copper Nanoparticles and the Toxicity towards Lung Epithelial Cells. Nanotoxicology 2011, 5 (2), 269– 281, DOI: 10.3109/17435390.2010.53626834Effect of sonication and serum proteins on copper release from copper nanoparticles and the toxicity towards lung epithelial cellsCronholm, Pontus; Midander, Klara; Karlsson, Hanna L.; Elihn, Karine; Wallinder, Inger Odnevall; Moeller, LennartNanotoxicology (2011), 5 (2), 269-281CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)Different methodol. settings can influence particle characteristics and toxicity in nanotoxicol. The aim of this study was to investigate how serum proteins and sonication of Cu nanoparticle suspensions influence the properties of the nanoparticles and toxicol. responses on human lung epithelial cells. This was investigated by using methods for particle characterization (photon correlation spectroscopy and TEM) and Cu release (at. absorption spectroscopy) in combination with assays for analyzing cell toxicity (MTT-, trypan blue- and Comet assay). The results showed that sonication of Cu nanoparticles caused decreased cell viability and increased Cu release compared to non-sonicated particles. Furthermore, serum in the cell medium resulted in less particle agglomeration and increased Cu release compared with medium without serum, but no clear difference in toxicity was detected. Few cells showed intracellular Cu nanoparticles due to fast release/dissoln. processes of Cu. In conclusion; sonication can affect the toxicity of nanoparticles.
- 34Laha, D.; Pramanik, A.; Laskar, A.; Jana, M.; Pramanik, P.; Karmakar, P. Shape-Dependent Bactericidal Activity of Copper Oxide Nanoparticle Mediated by DNA and Membrane Damage. Mater. Res. Bull. 2014, 59, 185– 191, DOI: 10.1016/j.materresbull.2014.06.02435Shape-dependent bactericidal activity of copper oxide nanoparticle mediated by DNA and membrane damageLaha, Dipranjan; Pramanik, Arindam; Laskar, Aparna; Jana, Madhurya; Pramanik, Panchanan; Karmakar, ParimalMaterials Research Bulletin (2014), 59 (), 185-191CODEN: MRBUAC; ISSN:0025-5408. (Elsevier Ltd.)In this work, we synthesized spherical and sheet shaped copper oxide nanoparticles and their phys. characterizations were done by the X-ray diffraction, fourier transform IR spectroscopy, transmission electron microscopy and dynamic light scattering. The antibacterial activity of these nanoparticles was detd. on both gram pos. and gram neg. bacterial. Spherical shaped copper oxide nanoparticles showed more antibacterial property on gram pos. bacteria where as sheet shaped copper oxide nanoparticles are more active on gram neg. bacteria. We also demonstrated that copper oxide nanoparticles produced reactive oxygen species in both gram neg. and gram pos. bacteria. Furthermore, they induced membrane damage as detd. by at. force microscopy and SEM. Thus prodn. of and membrane damage are major mechanisms of the bactericidal activity of these copper oxide nanoparticles. Finally it was concluded that antibacterial activity of nanoparticles depend on physicochem. properties of copper oxide nanoparticles and bacterial strain.
- 35Betancourt-Galindo, R.; Reyes-Rodriguez, P. Y.; Puente-Urbina, B. A.; Avila-Orta, C. A.; Rodríguez-Fernández, O. S.; Cadenas-Pliego, G.; Lira-Saldivar, R. H.; García-Cerda, L. A. Synthesis of Copper Nanoparticles by Thermal Decomposition and Their Antimicrobial Properties. J. Nanomater. 2014, 980545, DOI: 10.1155/2014/98054536Synthesis of copper nanoparticles by thermal decomposition and their antimicrobial propertiesBetancourt-Galindo, R.; Reyes-Rodriguez, P. Y.; Puente-Urbina, B. A.; Avila-Orta, C. A.; Rodriguez-Fernandez, O. S.; Cadenas-Pliego, G.; Lira-Saldivar, R. H.; Garcia-Cerda, L. A.Journal of Nanomaterials (2014), (), 980545/1-980545/6, 6CODEN: JNOABP; ISSN:1687-4129. (Hindawi Publishing Corp.)Copper nanoparticles were synthesized by thermal decompn. using copper chloride, sodium oleate, and Ph ether as solvent agents.The formation of nanoparticles was evidenced by the X-ray diffraction and transmission electron microscopy. The peaks in the XRD pattern correspond to the std. values of the fcc. (fcc) structure of metallic copper and no peaks of other impurity cryst. phases were detected. TEM anal. showed spherical nanoparticles with sizes in the range of 4 to 18 nm. The antibacterial properties of copper nanoparticles were evaluated in vitro against strains of Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial activity of copper nanoparticles synthesized by thermal decompn. showed significant inhibitory effect against these highly multidrug-resistant bacterial strains.
- 36Zhou, J.; Xiang, H.; Zabihi, F.; Yu, S.; Sun, B.; Zhu, M. Intriguing Anti-Superbug Cu2O@ZrP Hybrid Nanosheet with Enhanced Antibacterial Performance and Weak Cytotoxicity. Nano Res. 2019, 12 (6), 1453– 1460, DOI: 10.1007/s12274-019-2406-837Intriguing anti-superbug Cu2O@ZrP hybrid nanosheet with enhanced antibacterial performance and weak cytotoxicityZhou, Jialiang; Xiang, Hengxue; Zabihi, Fatemeh; Yu, Senlong; Sun, Bin; Zhu, MeifangNano Research (2019), 12 (6), 1453-1460CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)In view of it's strong antibacterial function and minor toxicity, cuprous oxide (Cu2O) is frequently used in various broad-spectrum antibacterial reagents. Nonetheless the undesirable effects of superbugs still remain challenging. In this research, a chem. deposition approach is used to prep. a Cu2O@ZrP composite with nanosheet configuration demonstrating excellent dispersibility and antibacterial traits. From systematic anal., it was inffered that the content of copper in the nanosheet was about 57-188 mg/g while the av. thickness of the nanosheets Cu2O formed on ZrP is approx. 0.8 nm. The results of the minimal inhibitory concn. (MIC) revealed that an extremely low loading of Cu2O in Cu2O@ZrP nanosheet can lead to exceptional antibacterial activity. Examd. on two various superbugs; i.e. methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE), the composite nanosheet reagent performed over 99% microbial redn. More intesetingly, the cell growth rate of the Cu2O@ZrP nanosheet was detd. to be 20% lower than that of the neat Cu2O, manifesting a weaker cytotoxicity. This unique hybrid nanosheet with intriguing anti-superbug performance promises highly efficient protection for the fabrics, battledress, and medical textiles.
- 37Shalom, Y.; Perelshtein, I.; Perkas, N.; Gedanken, A.; Banin, E. Catheters Coated with Zn-Doped CuO Nanoparticles Delay the Onset of Catheter-Associated Urinary Tract Infections. Nano Res. 2017, 10 (2), 520– 533, DOI: 10.1007/s12274-016-1310-838Catheters coated with Zn-doped CuO nanoparticles delay the onset of catheter-associated urinary tract infectionsShalom, Yakov; Perelshtein, Ilana; Perkas, Nina; Gedanken, Aharon; Banin, EhudNano Research (2017), 10 (2), 520-533CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)Catheter-assocd. urinary tract infections (CAUTIs) are among the most common bacterial infections assocd. with medical devices. In the current study, the synthesis, coating, antibiofilm properties, and biocompatibility of urinary catheters coated with Zn-doped CuO (Zn0.12Cu0.88O) nanoparticles (NPs) were examd. The doped NPs were synthesized and subsequently deposited on the catheter by the sonochem. method. The coated catheters displayed high antibiofilm activity and promising biocompatibility, as indicated by low in vitro cytotoxicity, negligible assocd. cytokine secretion, and absence of detectable irritation. The biocompatibility and ability of the Zn-doped CuO coating to inhibit biofilm formation were also evaluated in vivo using a rabbit model. Rabbits catheterized with uncoated catheters scored pos. for CAUTI by day 4 of the expt. In contrast, rabbits catheterized with Zn-doped CuO-coated catheters did not exhibit CAUTI until day 7 or remained completely uninfected for the whole duration of the 7-day expt. Furthermore, the in vivo biocompatibility assays and examns. supported the biosafety of Zn-doped CuO-coated catheters. Taken together, these data highlight the potential of Zn-doped CuO nanocomposite as effective antibiofilm compd.[Figure not available: see fulltext.].
- 38El-Batal, A. I.; Al-Hazmi, N. E.; Mosallam, F. M.; El-Sayyad, G. S. Biogenic Synthesis of Copper Nanoparticles by Natural Polysaccharides and Pleurotus Ostreatus Fermented Fenugreek Using Gamma Rays with Antioxidant and Antimicrobial Potential towards Some Wound Pathogens. Microb. Pathog. 2018, 118, 159– 169, DOI: 10.1016/j.micpath.2018.03.01339Biogenic synthesis of copper nanoparticles by natural polysaccharides and Pleurotus ostreatus fermented fenugreek using gamma rays with antioxidant and antimicrobial potential towards some wound pathogensEl-Batal, Ahmed I.; Al-Hazmi, Nawal E.; Mosallam, Farag M.; El-Sayyad, Gharieb S.Microbial Pathogenesis (2018), 118 (), 159-169CODEN: MIPAEV; ISSN:0882-4010. (Elsevier Ltd.)Mono-dispersed copper nanoparticles (CuNPs) were constructed using cheap polysaccharides (citrus pectin, chitosan, and sodium alginate), and by appropriating aq. fermented fenugreek powder (FFP) under the action of Pleurotus ostreatus (as reducing and preserving means), through the influence of gamma irradn. The synthesized CuNPs are described by UV-Vis. spectroscopy TEM, DLS, XRD, and FT-IR. XRD study of the CuNPs confirmed the generation of metallic CuNPs. The nucleation and the prodn. mechanism of CuNPs are moreover explained. TEM unveiled that, the ordinary diam. of CuNPs incorporated by various polysaccharides, and FFP taken in the range of 31.0 and 36.0 nm resp. CuNPs size is influenced by many parameters such as the variety of stabilizer, pH within the organization and applied gamma dose. Evaluation of the antioxidant and antimicrobial activities of CuNPs was performed against some selected wound pathogens. The results showed that, CuNPs were a strong antimicrobial agents against microbes caused burn skin infection such as Klebsiella pneumoniae, Staphylococcus aureus, and Candida albicans (16.0, 15.0, and 15.0 mm ZOI, resp.). Addnl., CuNPs have a strong antioxidant with 70% scavenging activity against DPPH. So, due to unique characteristics of CuNPs (cost-effective with continued-term stabilization and effective features), they can recover reasonable potential in biomedical, industrial, agricultural, cosmetics, dermal products and pharmaceutical purposes.
- 39Rubilar, O.; Rai, M.; Tortella, G.; Diez, M. C.; Seabra, A. B.; Durán, N. Biogenic Nanoparticles: Copper, Copper Oxides, Copper Sulphides, Complex Copper Nanostructures and Their Applications. Biotechnol. Lett. 2013, 35, 1365– 1375, DOI: 10.1007/s10529-013-1239-x40Biogenic nanoparticles: copper, copper oxides, copper sulphides, complex copper nanostructures and their applicationsRubilar, Olga; Rai, Mahendra; Tortella, Gonzalo; Diez, Maria Cristina; Seabra, Amedea B.; Duran, NelsonBiotechnology Letters (2013), 35 (9), 1365-1375CODEN: BILED3; ISSN:0141-5492. (Springer)A review. Copper nanoparticles have been the focus of intensive study due to their potential applications in diverse fields including biomedicine, electronics, and optics. Copper-based nanostructured materials have been used in conductive films, lubrification, nanofluids, catalysis, and also as potent antimicrobial agent. The biogenic synthesis of metallic nanostructured nanoparticles is considered to be a green and eco-friendly technol. since neither harmful chems. nor high temps. are involved in the process. The present review discusses the synthesis of copper nanostructured nanoparticles by bacteria, fungi, and plant exts., showing that biogenic synthesis is an economically feasible, simple and non-polluting process. Applications for biogenic copper nanoparticles are also discussed.
- 40Shobha, G.; Moses, V.; Ananda, S. Biological Synthesis of Copper Nanoparticles and Its Impact - A Review. Int. J. Pharm. Sci. Invent. 2014, 3 (8), 28– 38There is no corresponding record for this reference.
- 41Rafique, M.; Shaikh, A. J.; Rasheed, R.; Tahir, M. B.; Bakhat, H. F.; Rafique, M. S.; Rabbani, F. A Review on Synthesis, Characterization and Applications of Copper Nanoparticles Using Green Method. Nano 2017, 12 (4), 1750043, DOI: 10.1142/S179329201750043642A Review on Synthesis, Characterization and Applications of Copper Nanoparticles Using Green MethodRafique, Muhammad; Shaikh, Ahson J.; Rasheed, Reena; Tahir, Muhammad Bilal; Bakhat, Hafiz Faiq; Rafique, Muhammad Shahid; Rabbani, FaizNano (2017), 12 (4), 1750043CODEN: NANOFJ; ISSN:1793-2920. (World Scientific Publishing Co. Pte. Ltd.)To address accosts of this modern age, the synthesis of metal nanoparticles is more important than ever. Copper has been recognized as a nontoxic, safe inorg. material, cheaper antibacterial/antifungal agent, and has high potential in a wide range of biol., catalytic and sensors applications more particularly in the form of nanoparticles. This resulted in the development of numerous methods for the synthesis of copper nanoparticles. As conventional methods like chem. and phys. methods have several limitations so there is need to an alternate method. Due to nontoxic and eco-friendly nature, it has recently been shifted toward green synthesis of copper nanoparticles over conventional methods. Addnl., characterization of the synthesized nanoparticles is essential for their use in various applications. This review gives an overview of environment friendly synthesis method of copper nanoparticles and their applications on the basis of their potential selectivity and preferences in a no. of fields like material sciences and biomedicine.
- 42Delgado, K.; Quijada, R.; Palma, R.; Palza, H. Polypropylene with Embedded Copper Metal or Copper Oxide Nanoparticles as a Novel Plastic Antimicrobial Agent. Lett. Appl. Microbiol. 2011, 53, 50– 54, DOI: 10.1111/j.1472-765X.2011.03069.x4300Polypropylene with embedded copper metal or copper oxide nanoparticles as a novel plastic antimicrobial agentDelgado, K.; Quijada, R.; Palma, R.; Palza, H.Letters in Applied Microbiology (2011), 53 (1), 50-54CODEN: LAMIE7; ISSN:0266-8254. (Wiley-Blackwell)Aims: To develop novel polypropylene composite materials with antimicrobial activity by adding different types of copper nanoparticles. Methods and Results: Copper metal (CuP) and copper oxide nanoparticles (CuOP) were embedded in a polypropylene (PP) matrix. These composites present strong antimicrobial behavior against E. coli that depends on the contact time between the sample and the bacteria. After just 4 h of contact, these samples are able to kill more than 95% of the bacteria. CuOP fillers are much more effective eliminating bacteria than CuP fillers, showing that the antimicrobial property further depends on the type of copper particle. Cu2+ released from the bulk of the composite is responsible for this behavior. Moreover, PP/CuOP composites present a higher release rate than PP/CuP composites in a short time, explaining the antimicrobial tendency. Conclusions: Polypropylene composites based on copper nanoparticles can kill E. coli bacteria depending on the release rate of Cu2+ from the bulk of the material. CuOP are more effective as antimicrobial filler than CuP. Significance and Impact of the Study: Our findings open up novel applications of these ion-copper-delivery plastic materials based on PP with embedded copper nanoparticles with great potential as antimicrobial agents.
- 43Xiao, J.; Zhu, Y.; HUddleston, S.; Li, P.; Xiao, B.; Farha, O. K.; Ameer, G. A. Copper Metal−Organic Framework Nanoparticles Stabilized with Folic Acid Improve Wound Healing in Diabetes. ACS Nano 2018, 12, 1023– 1032, DOI: 10.1021/acsnano.7b018504301Copper Metal-Organic Framework Nanoparticles Stabilized with Folic Acid Improve Wound Healing in DiabetesXiao, Jisheng; Zhu, Yunxiao; Huddleston, Samantha; Li, Peng; Xiao, Baixue; Farha, Omar K.; Ameer, Guillermo A.ACS Nano (2018), 12 (2), 1023-1032CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper-based metal-org. framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solns., can be modified to slowly release Cu2+, resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addn., cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu2+ release, thus enabling the direct application of Cu-MOF NPs to wounds.
- 44Rasool, U.; Hemalatha, S. Marine Endophytic Actinomycetes Assisted Synthesis of Copper Nanoparticles (CuNPs): Characterization and Antibacterial Efficacy against Human Pathogens. Mater. Lett. 2017, 194, 176– 180, DOI: 10.1016/j.matlet.2017.02.05543Marine endophytic actinomycetes assisted synthesis of copper nanoparticles (CuNPs): Characterization and antibacterial efficacy against human pathogensRasool, Ubaid; Hemalatha, S.Materials Letters (2017), 194 (), 176-180CODEN: MLETDJ; ISSN:0167-577X. (Elsevier B.V.)Marine endophytic actinomycetes isolated from seaweeds was used in assisting the synthesis of copper nanoparticles which were characterized by UV-Visible spectroscopy, FTIR, SEM, TEM, and assessed for antibacterial activity against 5 different human pathogenic bacteria. Freshly synthesized copper nanoparticles showed 2 absorption bands at 370 nm and 690 nm due to their variable size. FTIR anal. confirmed the capping and stabilization, SEM anal. depicted the morphol., EDX anal. confirmed the presence and TEM anal. provided the size and shape of synthesized copper nanoparticles. Antibacterial activity was obsd. through zones of inhibition. The results suggested that copper nanoparticles synthesized by the assistance of actinomycetes can be utilized to control the human pathogenic bacteria.
- 45Bocarando-Chacón, J.; Vargas-Vazquez, D.; Martinez-Suarez, F.; Flores-Juárez, C.; Cortez-Valadez, M. Surface-Enhanced Raman Scattering and Antibacterial Properties from Copper Nanoparticles Obtained by Green Chemistry. Appl. Phys. A: Mater. Sci. Process. 2020, 126 (7), 530, DOI: 10.1007/s00339-020-03704-144Surface-enhanced Raman scattering and antibacterial properties from copper nanoparticles obtained by green chemistryBocarando-Chacon, J.; Vargas-Vazquez, D.; Martinez-Suarez, F.; Flores-Juarez, C.; Cortez-Valadez, M.Applied Physics A: Materials Science & Processing (2020), 126 (7), 530CODEN: APAMFC; ISSN:0947-8396. (Springer)In this study, copper nanoparticles (CuNPs) were synthesized using the ext. of Opuntia ficus-Indica and Geranium as a reducing agent. By transmission electron microscopy, the morphol. of the nanoparticles was detd. to be mostly spherical, with a particle size about 3-10 nm. The UV-Vis spectra displayed absorption bands between 525 and 550 nm, assocd. with the surface plasmon resonance in the CuNPs. The various particle sizes obtained were tested as SERS substrate with the pyridine mol. Antibacterial activity of copper nanoparticles against Escherichia coli gram-neg. bacteria was studied. Bacteriol. inhibition tests were performed on nutrient agar plates supplemented with different concns. of copper nanoparticles. The copper nanoparticles with a concn. of 150μg/mL and a size distribution around 6 nm showed the largest bactericidal effectiveness against E. coli.
- 46Amorim, A.; Mafud, A. C. pd; Nogueira, S.; Jesus, J. R.; Araújo, A. R.; de Plácido, A.; Brito Neta, M.; Alves, M. M. M.; Carvalho, F. A. A.; Rufino Arcanjo, D. D.; Braun, S.; López, M. S. P.; López-Ruiz, B.; Delerue-Matos, C.; Mascarenhas, Y.; Silva, D.; Eaton, P.; Almeida Leite, J. R. S. Copper Nanoparticles Stabilized with Cashew Gum: Antimicrobial Activity and Cytotoxicity against 4T1Mouse Mammary Tumor Cell Line. J. Biomater. Appl. 2019, 34 (2), 188– 197, DOI: 10.1177/088532821984596445Copper nanoparticles stabilized with cashew gum: Antimicrobial activity and cytotoxicity against 4T1 mouse mammary tumor cell lineAmorim, Adriany; Mafud, Ana Carolina; Nogueira, Silvania; Jesus, Joilson Ramos; de Araujo, Alyne Rodrigues; Placido, Alexandra; Brito Neta, Maria; Alves, Michel Mualem Moraes; Carvalho, Fernando Aecio Amorim; Rufino Arcanjo, Daniel Dias; Braun, Sacha; Lopez, Marta Sanchez-Paniagua; Lopez-Ruiz, Beatriz; Delerue-Matos, Cristina; Mascarenhas, Yvonne; Silva, Durcilene; Eaton, Peter; Almeida Leite, Jose Roberto SouzaJournal of Biomaterials Applications (2019), 34 (2), 188-197CODEN: JBAPEL; ISSN:0885-3282. (Sage Publications Ltd.)Copper nanoparticles stabilized with cashew (CG-CuNPs) were synthesized by redn. reaction using ascorbic acid and sodium borohydride, using the cashew gum (CG) as a natural polymer stabilizer. Dynamic light scattering, at. force microscopy, Fourier-transform IR spectroscopy, UV-Vis spectrophotometry, and x-ray diffraction were used to characterize the nanoparticles (CG-CuNPs), and copper was quantified by electrochem. measurement. The UV-vis spectra of the CG-CuNPs confirmed the formation of nanoparticles by appearance of a surface plasmon band at 580 nm after 24 h of reaction. The Fourier-transform IR spectrum of CG-CuNPs showed the peak at 1704 cm-1 from cashew gum, confirming the presence of the gum in the nanoparticles. The av. size of CG-CuNPs by dynamic light scattering and at. force microscopy was around 10 nm, indicating small, approx. spherical particles. Antimicrobial assays showed that CG-CuNPs had activity against Staphylococcus aureus ATCC 29213 with a minimal inhibitory concn. of 0.64 mM. The cytotoxicity assay on BALB/c murine macrophages showed lower cytotoxic effects for CG-CuNPs than CuSO4·5H2O. Viability cell assays for CG-CuNPs at (0.250 mM) inhibited by 70% the growth of 4T1 LUC (4T1 mouse mammary tumor cell line) and NIH 3T3 cells (murine fibroblast cells) over a 24-h period. Therefore, CG-CuNPs can be used as an antimicrobial agent with lower cytotoxic effects than the CuSO4·5H2O precursor.
- 47Zhao, H.; Su, H.; Ahmeda, A.; Sun, Y.; Li, Z.; Zangeneh, M. M.; Nowrozi, M.; Zangeneh, A.; Moradi, R. Biosynthesis of Copper Nanoparticles Using Allium Eriophyllum Boiss Leaf Aqueous Extract; Characterization and Analysis of Their Antimicrobial and Cutaneous Wound-Healing Potentials. Appl. Organomet. Chem. 2020, DOI: 10.1002/aoc.5587There is no corresponding record for this reference.
- 48Yaqub, A.; Malkani, N.; Shabbir, A.; Ditta, S. A.; Tanvir, F.; Ali, S.; Naz, M.; Kazmi, S. A. R.; Ullah, R. Novel Biosynthesis of Copper Nanoparticles Using Zingiber and Allium Sp. with Synergic Effect of Doxycycline for Anticancer and Bactericidal Activity. Curr. Microbiol. 2020, 77 (9), 2287– 2299, DOI: 10.1007/s00284-020-02058-447Novel Biosynthesis of Copper Nanoparticles Using Zingiber and Allium sp. with Synergic Effect of Doxycycline for Anticancer and Bactericidal ActivityYaqub, Atif; Malkani, Naila; Shabbir, Arifa; Ditta, Sarwar Allah; Tanvir, Fouzia; Ali, Shaista; Naz, Misbah; Kazmi, Syed Akif Raza; Ullah, RehanCurrent Microbiology (2020), 77 (9), 2287-2299CODEN: CUMIDD; ISSN:0343-8651. (Springer)Copper nanoparticles (CuNPs), due to their cost-effective synthesis, interesting properties, and a wide range of applications in conductive inks, cooling fluids, biomedical field, and catalysis, have attracted the attention of scientific community in recent years. The aim of the present study was to develop and characterize antibacterial and anticancer CuNPs synthesized via chem. and biol. methods, and further synthesize CuNPs conjugated with doxycycline to study their synergic effect. During the chem. synthesis, ascorbic acid was used as a stabilizing agent, while Zingiber officinale and Allium sativum-derived exts. were used during the biol. methods for synthesis of CuNPs. Characterization of CuNPs was performed by transmission electron microscopy (TEM), UV-visible spectroscopy, Fourier transform IR spectroscopy (FTIR), and X-ray crystallog. (XRD). Antimicrobial evaluation of the nanomaterials against Pseudomonas aeruginosa and Escherichia coli was performed by using disk diffusion method, while anticancer behavior against HeLa and HepG2 cell lines was studied by MTT assay. TEM revealed spherical-shaped nanoparticles with mean size of 22.70 ± 5.67, 35.01 ± 5.84, and 19.02 ± 2.41 nm for CuNPs, Gin-CuNPs, and Gar-CuNPs, resp., and surface plasmon resonance peaks were obtained at 570 nm, 575 nm, and 610 nm for CuNPs, Gar-CuNPs, and Gin-CuNPs, resp. The results of FTIR confirmed the consumption of biomols. from the plant exts. for the synthesis of CuNPs. XRD anal. also confirmed synthesis of CuNPs. Doxycycline-conjugated NPs exhibited more antibacterial effects than doxycycline or CuNPs alone. Copper nanoparticles prepd. by biol. synthesis are cost-effective and eco-friendly as compared to their chem. counterparts. The chem. synthesized nanoparticles displayed more significant antimicrobial activity when capped with doxycycline than Z. officinale and A. sativum-mediated CuNPs; however, green-synthesized nanoparticles showed greater anticancer activity than their chem. counterparts.
- 49Velnar, T.; Bailey, T.; Smrkolj, V. The Wound Healing Process: An Overview of the Cellular and Molecular Mechanisms. J. Int. Med. Res. 2009, 37, 1528– 1542, DOI: 10.1177/14732300090370053148The wound healing process: an overview of the cellular and molecular mechanismsVelnar, T.; Bailey, T.; Smrkolj, V.Journal of International Medical Research (2009), 37 (5), 1528-1542CODEN: JIMRBV; ISSN:0300-0605. (Field House Publishing LLP)A review. Wound healing remains a challenging clin. problem and correct, efficient wound management is essential. Much effort has been focused on wound care with an emphasis on new therapeutic approaches and the development of technologies for acute and chronic wound management. Wound healing involves multiple cell populations, the extracellular matrix and the action of sol. mediators such as growth factors and cytokines. Although the process of healing is continuous, it may be arbitrarily divided into four phases: (i) coagulation and haemostasis; (ii) inflammation; (iii) proliferation; and (iv) wound remodelling with scar tissue formation. The correct approach to wound management may effectively influence the clin. outcome. This review discusses wound classification, the physiol. of the wound healing process and the methods used in wound management.
- 50Kalashnikova, I.; Das, S.; Seal, S. Nanomaterials for Wound Healing: Scope and Advancement. Nanomedicine 2015, 10 (16), 2593– 2612, DOI: 10.2217/nnm.15.8249Nanomaterials for wound healing: scope and advancementKalashnikova, Irina; Das, Soumen; Seal, SudiptaNanomedicine (London, United Kingdom) (2015), 10 (16), 2593-2612CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Innovative methods for treating impaired and hard-to-heal wounds are needed. Novel strategies are needed for faster healing by reducing infection, moisturizing the wound, stimulating the healing mechanisms, speeding up the wound closure and reducing scar formation. In the past few years, nanotechnol. has been constantly revolutionizing the treatment and management of wound care, by offering novel solns. which include but are not limited to: state-of-the-art materials, so called 'smart' biomaterials and theranostic nanoparticles. Nanotechnol.-based therapy has recently announced itself as a possible next-generation therapy that is able to advance wound healing to cure chronic wounds. In this communication, the recent progress in advanced therapy for cutaneous wound healing during last 5 years using a nanotechnol.-based approach is summarized.
- 51Alizadeh, S.; Seyedalipour, B.; Shafieyan, S.; Kheime, A.; Mohammadi, P.; Aghdami, N. Copper Nanoparticles Promote Rapid Wound Healing in Acute Full Thickness Defect via Acceleration of Skin Cell Migration, Proliferation, and Neovascularization. Biochem. Biophys. Res. Commun. 2019, 517 (4), 684– 690, DOI: 10.1016/j.bbrc.2019.07.11050Copper nanoparticles promote rapid wound healing in acute full thickness defect via acceleration of skin cell migration, proliferation, and neovascularizationAlizadeh, Sanaz; Seyedalipour, Bagher; Shafieyan, Saeed; Kheime, Abolfazl; Mohammadi, Parvaneh; Aghdami, NasserBiochemical and Biophysical Research Communications (2019), 517 (4), 684-690CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Worldwide, impaired wound healing leads to a large burden of morbidity and mortality. Current treatments have several limitations. Recently, nanomaterials such as copper nanoparticles (CuNPs) have attracted considerable research interest. Here, we investigated the potential therapeutic effect of various CuNPs concns. (1μM, 10μM, 100μM, 1 mM, and 10 mM) and sizes (20 nm, 40 nm, 80 nm) in wound healing. Our results revealed that the 10μM concn. of 40 nm CuNPs and the 1μM concn. of 80 nm CuNPs were not toxic to the cultured fibroblast, endothelial, and keratinocyte cells, and also 1μM concn. of 80 nm CuNPs enhanced endothelial cell migration and proliferation. Extensive assessment of in-vivo wound healing demonstrated that the 1μM concn. of 80 nm CuNPs accelerated wound healing over a shorter time via formation of granulation tissue and higher new blood vessels. Importantly, serum biochem. anal. confirmed that the 40 nm CuNP (10μM) and 80 nm CuNP (1μM) did not show any accumulation in the liver during wound healing. Overall, our results have indicated that the 1μM concn. of 80 nm CuNPs is a promising NP for wound healing applications without adverse side effects.
- 52Sankar, R.; Baskaran, A.; Shivashangari, K. S.; Ravikumar, V. Inhibition of Pathogenic Bacterial Growth on Excision Wound by Green Synthesized Copper Oxide Nanoparticles Leads to Accelerated Wound Healing Activity in Wistar Albino Rats. J. Mater. Sci.: Mater. Med. 2015, 26, 214, DOI: 10.1007/s10856-015-5543-y51Inhibition of pathogenic bacterial growth on excision wound by green synthesized copper oxide nanoparticles leads to accelerated wound healing activity in Wistar Albino ratsSankar Renu; Baskaran Athmanathan; Shivashangari Kanchi Subramanian; Ravikumar VilwanathanJournal of materials science. Materials in medicine (2015), 26 (7), 214 ISSN:.An impaired wound healing is one of the major health related problem in diabetic and non-diabetic patients around the globe. The pathogenic bacteria play a predominant role in delayed wound healing, owing to interaction in the wound area. In our previous work we developed green chemistry mediated copper oxide nanoparticles using Ficus religiosa leaf extract. In the present study we make an attempt to evaluate the anti-bacterial, and wound healing activity of green synthesized copper oxide nanoparticles in male Wistar Albino rats. The agar well diffusion assay revealed copper oxide nanoparticles have substantial inhibition activity against human pathogenic strains such as Klebsiella pneumoniae, Shigella dysenteriae, Staphylococcus aureus, Salmonella typhimurium and Escherichia coli, which were responsible for delayed wound healing process. Furthermore, the analyses results of wound closure, histopathology and protein profiling confirmed that the F. religiosa leaf extract tailored copper oxide nanoparticles have enhanced wound healing activity in Wistar Albino rats.
- 53Zangeneh, M. M.; Ghaneialvar, H.; Akbaribazm, M.; Ghanimatdan, M.; Abbasi, N.; Goorani, S.; Pirabbasi, E.; Zangeneh, A. Novel Synthesis of Falcaria Vulgaris Leaf Extract Conjugated Copper Nanoparticles with Potent Cytotoxicity, Antioxidant, Antifungal, Antibacterial, and Cutaneous Wound Healing Activities under in Vitro and in Vivo Condition. J. Photochem. Photobiol., B 2019, 197, 111556, DOI: 10.1016/j.jphotobiol.2019.11155652Novel synthesis of falcaria vulgaris leaf extract conjugated copper nanoparticles with potent cytotoxicity, antioxidant, antifungal, antibacterial, and cutaneous wound healing activities under in vitro and in vivo conditionZangeneh, Mohammad Mahdi; Ghaneialvar, Hori; Akbaribazm, Mohsen; Ghanimatdan, Mohamad; Abbasi, Naser; Goorani, Samaneh; Pirabbasi, Elham; Zangeneh, AkramJournal of Photochemistry and Photobiology, B: Biology (2019), 197 (), 111556CODEN: JPPBEG; ISSN:1011-1344. (Elsevier B.V.)The aim of this study was green synthesis of copper nanoparticles from aq. ext. of Falcaria vulgaris leaf and assessment of their cytotoxicity, antioxidant, antifungal, antibacterial, and cutaneous wound healing properties. The synthesized CuNPs had great cell viability dose-dependently Investigating the effect of the CuNPs on HUVEC cell line and indicated this method was nontoxic. In part of cutaneous wound healing property of CuNPs, after creating the cutaneous wound, the rats were randomly divided into six groups: treatment with 0.2% CuNPs ointment, treatment with 0.2% CuSO4 ointment, treatment with 0.2% F. vulgaris ointment, treatment with 3% tetracycline ointment, treatment with Eucerin basal ointment, and untreated control. Treatment with CuNPs ointment remarkably increased (p ≤ .01) the wound contracture, vessel, hexosamine, hydroxyl proline, hexuronic acid, fibrocyte, and fibrocytes/fibroblast rate and substantially reduced (p ≤ .01) the wound area, total cells, neutrophil, and lymphocyte compared to other groups. In case of antibacterial effects of CuNPs, they inhibited the growth of all bacteria at 2-8 mg/mL concns. and removed them at 4-16 mg/mL concns. (p ≤ .01). The results of XRD, FT-IR, UV, TEM, and FE-SEM confirm that the aq. ext. of F. vulgaris leaf can be used to yield copper nanoparticles with notable amt. of antioxidant, antifungal, antibacterial, and cutaneous wound healing potentials without any cytotoxicity.
- 54Gopal, A.; Kant, V.; Gopalakrishnan, A.; Tandan, S. K.; Kumar, D. Chitosan-Based Copper Nanocomposite Accelerates Healing in Excision Wound Model in Rats. Eur. J. Pharmacol. 2014, 731 (1), 8– 19, DOI: 10.1016/j.ejphar.2014.02.03353Chitosan-based copper nanocomposite accelerates healing in excision wound model in ratsGopal, Anu; Kant, Vinay; Gopalakrishnan, Anu; Tandan, Surendra K.; Kumar, DineshEuropean Journal of Pharmacology (2014), 731 (), 8-19CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Copper possesses efficacy in wound healing which is a complex phenomenon involving various cells, cytokines and growth factors. Copper nanoparticles modulate cells, cytokines and growth factors involved in wound healing in a better way than copper ions. Chitosan has been shown to be beneficial in healing because of its antibacterial, antifungal, biocompatible and biodegradable polymeric nature. In the present study, chitosan-based copper nanocomposite (CCNC) was prepd. by mixing chitosan and copper nanoparticles. CCNC was applied topically to evaluate its wound healing potential and to study its effects on some important components of healing process in open excision wound model in adult Wistar rats. Significant increase in wound contraction was obsd. in the CCNC-treated rats. The up-regulation of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1(TGF-β1) by CCNC-treatment revealed its role in facilitating angiogenesis, fibroblast proliferation and collagen deposition. The tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were significantly decreased and increased, resp., in CCNC-treated rats. Histol. evaluation showed more fibroblast proliferation, collagen deposition and intact re-epithelialization in CCNC-treated rats. Immunohistochem. of CD31 revealed marked increase in angiogenesis. Thus, we concluded that chitosan-based copper nanocomposite efficiently enhanced cutaneous wound healing by modulation of various cells, cytokines and growth factors during different phases of healing process.
- 55Tao, B.; Lin, C.; Deng, Y.; Yuan, Z.; Shen, X.; Chen, M.; He, Y.; Peng, Z.; Hu, Y.; Cai, K. Copper-Nanoparticle-Embedded Hydrogel for Killing Bacteria and Promoting Wound Healing with Photothermal Therapy. J. Mater. Chem. B 2019, 7 (15), 2534– 2548, DOI: 10.1039/C8TB03272F54Copper-nanoparticle-embedded hydrogel for killing bacteria and promoting wound healing with photothermal therapyTao, Bailong; Lin, Chuanchuan; Deng, Yiman; Yuan, Zhang; Shen, Xinkun; Chen, Maowen; He, Ye; Peng, Zhihong; Hu, Yan; Cai, KaiyongJournal of Materials Chemistry B: Materials for Biology and Medicine (2019), 7 (15), 2534-2548CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Bacterial infections at wound tissue sites usually delay the wound healing process and even result in severe life-threatening complications. Therefore, it is imperative to develop an efficient strategy to simultaneously enhance the antibacterial abilities and improve the wound healing process. Here, we report a composite hydrogel composed of methacrylate-modified gelatin (Gel-MA) and N,N-bis(acryloyl)cystamine (BACA)-chelated Cu nanoparticles (Cu NPs) via radical polymn. with a photoinitiator. The Cu NPs could effectively convert NIR laser irradn. (808 nm) energy into localized heat due to the localized surface plasmon resonance (LSPR) effect for effecting photothermal therapy. In vitro antimicrobial expts. revealed that the hybrid hydrogel exhibited predominant antibacterial efficacy against both Gram-pos. (Staphylococcus aureus) and Gram-neg. (Escherichia coli) bacteria, while Cu-NP-embedded hydrogel + laser group exhibited superior antibacterial capacity. The excellent antibacterial properties can be attributed to the synergistic effect of photothermal performance and rapid release of copper ions (Cu2+) because of the laser irradn. of Cu NPs. Moreover, the released Cu2+ could stimulate NIH-3T3 fibroblast proliferation without any inflammatory responses. Moreover, chronic wound healing process of S. aureus-infected model was significantly accelerated with prominent antibacterial ability, reduced inflammatory response, and promoted angiogenesis ability in vivo. In summary, Cu-NP-embedded hydrogels are a promising candidate for skin tissue regeneration and potentially valuable for clin. applications.
- 56Rajendran, N. K.; Kumar, S. S. D.; Houreld, N. N.; Abrahamse, H. A Review on Nanoparticle Based Treatment for Wound Healing. J. Drug Delivery Sci. Technol. 2018, 44, 421– 430, DOI: 10.1016/j.jddst.2018.01.00955A review on nanoparticle based treatment for wound healingRajendran, Naresh Kumar; Kumar, Sathish Sundar Dhilip; Houreld, Nicolette Nadene; Abrahamse, HeidiJournal of Drug Delivery Science and Technology (2018), 44 (), 421-430CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)Wound care management relies mainly on the development of new and effective wound dressing materials, and it continues to be an intense area of research in chronic wound care. Proper wound care management is a significant clin. challenge and there is a growing need for wound care. In recent years, the research and development of wound dressing materials have entered a new level of stds. and there is a far better understanding based on the pathogenesis of chronic wounds. Nanotechnol. offers a superlative approach to hasten the healing of acute and chronic wounds, by stimulating proper movement through the different healing phases. In nanotechnol., the small sized nanomaterials, nanoscaffolds, nanofibers and biomaterials are used for topical drug delivery for wound healing. In recent years, the use of nanomaterials for biomedical and pharmaceutical applications have gained significant attraction. Thus, a considerable percentage of nanomaterials are used in various biomedical applications for wound dressings, drug delivery and other medical purposes. This review is an attempt to illustrate the use of nanoparticles and biodegradable nanomaterials in wound healing. Addnl., the present status of nanoparticles delivery of exogenous growth factors and peptide structures in clin. trials are also reviewed in this manuscript.
- 57Kaplan, J. H.; Maryon, E. B. How Mammalian Cells Acquire Copper: An Essential but Potentially Toxic Metal. Biophys. J. 2016, 110 (1), 7– 13, DOI: 10.1016/j.bpj.2015.11.02556How mammalian cells acquire copper: An essential but potentially toxic metalKaplan, Jack H.; Maryon, Edward B.Biophysical Journal (2016), 110 (1), 7-13CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)A review. Cu is an essential micronutrient, and its role in an array of crit. physiol. processes is receiving increasing attention. Among these are wound healing, angiogenesis, protection against reactive O species, neurotransmitter synthesis, modulation of normal cell and tumor growth, and many others. Free Cu is absent inside cells, and a network of proteins has evolved to deliver this essential, but potentially toxic, metal ion to its intracellular target sites following uptake. Although the total body content is low (∼100 mg), dysfunction of proteins involved in Cu homeostasis results in several well-characterized human disease states. The initial step in cellular Cu handling is its transport across the plasma membrane, a subject of study for only about the last 25 yr. Here, the authors focus on the initial step in Cu homeostasis, the properties of the major protein, hCTR1, that mediates Cu uptake, and the status of the understanding of this highly specialized transport system. Although a high-resoln. structure of the protein is still lacking, an array of biochem. and biophys. studies have provided a picture of how hCTR1 mediates Cu(I) transport and how Cu is delivered to the proteins in the intracellular milieu. Recent studies provide evidence that the transporter also plays a key protective role in the regulation of cellular Cu via regulatory endocytosis, lowering its surface expression, in response to elevated Cu loads.
- 58Ashino, T.; Sudhahar, V.; Urao, N.; Oshikawa, J.; Chen, G. F.; Wang, H.; Huo, Y.; Finney, L.; Vogt, S.; McKinney, R. D.; Maryon, E. B.; Kaplan, J. H.; Ushio-Fukai, M.; Fukai, T. Unexpected Role of the Copper Transporter ATP7A in PDGF-Induced Vascular Smooth Muscle Cell Migration. Circ. Res. 2010, 107 (6), 787– 799, DOI: 10.1161/CIRCRESAHA.110.22533457Unexpected Role of the Copper Transporter ATP7A in PDGF-Induced Vascular Smooth Muscle Cell MigrationAshino, Takashi; Sudhahar, Varadarajan; Urao, Norifumi; Oshikawa, Jin; Chen, Gin-Fu; Wang, Huan; Huo, Yuqing; Finney, Lydia; Vogt, Stefan; McKinney, Ronald D.; Maryon, Edward B.; Kaplan, Jack H.; Ushio-Fukai, Masuko; Fukai, TohruCirculation Research (2010), 107 (6), 787-799CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans-Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation. To det. the role of copper transporter ATP7A in PDGF-induced VSMC migration. Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addn., ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was obsd. by synchrotron-based x-ray fluorescence microscopy at neointimal VSMCs in wire injury model. These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis.
- 59Pickart, L.; Vasquez-Soltero, J. M.; Margolina, A. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. BioMed. Res. Int. 2015, 2015, 648108, DOI: 10.1155/2015/64810858GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin RegenerationPickart Loren; Vasquez-Soltero Jessica Michelle; Margolina AnnaBioMed research international (2015), 2015 (), 648108 ISSN:.GHK (glycyl-L-histidyl-L-lysine) is present in human plasma, saliva, and urine but declines with age. It is proposed that GHK functions as a complex with copper 2+ which accelerates wound healing and skin repair. GHK stimulates both synthesis and breakdown of collagen and glycosaminoglycans and modulates the activity of both metalloproteinases and their inhibitors. It stimulates collagen, dermatan sulfate, chondroitin sulfate, and the small proteoglycan, decorin. It also restores replicative vitality to fibroblasts after radiation therapy. The molecule attracts immune and endothelial cells to the site of an injury. It accelerates wound-healing of the skin, hair follicles, gastrointestinal tract, boney tissue, and foot pads of dogs. It also induces systemic wound healing in rats, mice, and pigs. In cosmetic products, it has been found to tighten loose skin and improve elasticity, skin density, and firmness, reduce fine lines and wrinkles, reduce photodamage, and hyperpigmentation, and increase keratinocyte proliferation. GHK has been proposed as a therapeutic agent for skin inflammation, chronic obstructive pulmonary disease, and metastatic colon cancer. It is capable of up- and downregulating at least 4,000 human genes, essentially resetting DNA to a healthier state. The present review revisits GHK's role in skin regeneration in the light of recent discoveries.
- 60Sen, C. K.; Khanna, S.; Venojarvi, M.; Trikha, P.; Christopher Ellison, E.; Hunt, T. K.; Roy, S. Copper-Induced Vascular Endothelial Growth Factor Expression and Wound Healing. Am. J. Physiol. - Heart Circ. Physiol. 2002, 282 (5), 1821– 1827, DOI: 10.1152/ajpheart.01015.2001There is no corresponding record for this reference.
- 61Wang, W.; Post, J. I.; Dow, K. E.; Shin, S. H.; Riopelle, R. J.; Ross, G. M. Zinc and Copper Inhibit Nerve Growth Factor-Mediated Protection from Oxidative Stress-Induced Apoptosis. Neurosci. Lett. 1999, 259 (2), 115– 118, DOI: 10.1016/S0304-3940(98)00929-X60Zinc and Copper inhibit nerve growth factor-mediated protection from oxidative stress-induced apoptosisWang, Wei; Post, Joan I.; Dow, Kimberly E.; Shin, Seon H.; Riopelle, Richard J.; Ross, Gregory M.Neuroscience Letters (1999), 259 (2), 115-118CODEN: NELED5; ISSN:0304-3940. (Elsevier Science Ireland Ltd.)We have previously provided evidence that two transition metal cations, Zn2+ and Cu2+, can alter the conformation of nerve growth factor (NGF), rendering it unable to bind to its receptors or to activate signal transduction pathways. In the present study, we have assessed the influence of Zn2+ and Cu2+ on NGF-mediated protection from an oxidative insult. Exposure of rat pheochromocytoma (PC12) cells to hydrogen peroxide resulted in an increase in cell death via apoptosis, which was inhibited by NGF. Zn2+ and Cu2+, when added to cultures at a concn. of 100 μM, prevented NGF-mediated survival-promoting effects. Neither of these ions had an effect on basal cell viability (in the absence of NGF) after an oxidative insult. These results demonstrate that Zn2+ and Cu2+ can selectively inhibit NGF-mediated resistance to an oxidative stress, and have significant implications for neuronal function under both physiol. and pathol. (e.g. cerebral ischemia) conditions.
- 62Tahvilian, R.; Zangeneh, M. M.; Falahi, H.; Sadrjavadi, K.; Jalalvand, A. R.; Zangeneh, A. Green Synthesis and Chemical Characterization of Copper Nanoparticles Using Allium Saralicum Leaves and Assessment of Their Cytotoxicity, Antioxidant, Antimicrobial, and Cutaneous Wound Healing Properties. Appl. Organomet. Chem. 2019, 33 (12), e5234, DOI: 10.1002/aoc.523463Green synthesis and chemical characterization of copper nanoparticles using Allium saralicum leaves and assessment of their cytotoxicity, antioxidant, antimicrobial, and cutaneous wound healing propertiesTahvilian, Reza; Zangeneh, Mohammad Mahdi; Falahi, Homeyra; Sadrjavadi, Komail; Jalalvand, Ali R.; Zangeneh, AkramApplied Organometallic Chemistry (2019), 33 (12), e5234CODEN: AOCHEX; ISSN:0268-2605. (John Wiley & Sons Ltd.)In recent decades, nanotechnol. is growing rapidly owing to its widespread application in science and industry. The aim of the expt. was the green synthesis of copper nanoparticles using Allium saralicum R.M. Fritsch aq. ext. and assessment of their cytotoxicity, antioxidant, antibacterial, antifungal, and cutaneous wound healing effects under in vitro and in vivo conditions. These nanoparticles were characterized by Fourier transformed IR spectroscopy (FT-IR), UV-visible spectroscopy, field emission SEM (FE-SEM), transmission electron microscopy (TEM), and at. force microscopy (AFM). DPPH free radical scavenging test was done to assess the antioxidant properties, which indicated similar antioxidant potentials for CuNPs@Allium and butylated hydroxytoluene. Min. Inhibitory Concn. (MIC), Min. Bactericidal Concn. (MBC), and Min. Fungicidal Concn. (MFC) were specified by macro-broth diln. assay. CuNPs@Allium indicated higher antibacterial and antifungal effects than all std. antibiotics (p ≤ 0.01). Also, CuNPs@Allium inhibited the growth of all bacteria at 1-8 mg/mL concns. and removed them at 2-8 mg/mL concns. (p ≤ 0.01). In the case of antifungal properties of CuNPs@Allium, they prevented the growth of all fungi at 1-4 mg/mL concns. and destroyed them at 2-8 mg/mL concns. (p ≤ 0.01). In vivo expt., after creating the cutaneous wound, the rats were randomly divided into six groups (n = 10): untreated control, treatment with Eucerin basal ointment, treatment with 3% tetracycline ointment, treatment with 0.2% CuSO4 ointment, treatment with 0.2% A. saralicum ointment, and treatment with 0.2% CuNPs@Allium ointment. Use of CuNPs@Allium ointment in the treatment groups substantially reduced (p ≤ 0.01) the wound area, total cells, neutrophil, macrophage, and lymphocyte and remarkably raised (p ≤ 0.01) the wound contracture, hydroxyl proline, hexosamine, hexuronic acid, fibrocyte, and fibrocytes/fibroblast rate compared to other groups. The synthesized CuNPs@Allium had high cell viability dose-dependently (Investigating the effect of the plant on HUVEC cell line) and revealed this method was nontoxic. The results revealed the useful non-cytotoxic, antioxidant, antibacterial, antifungal, and cutaneous wound healing effects of CuNPs@Allium.
- 63Tu, Y.; Lv, M.; Xiu, P.; Huynh, T.; Zhang, M.; Castelli, M.; Liu, Z.; Huang, Q.; Fan, C.; Fang, H.; Zhou, R. Destructive Extraction of Phospholipids from Escherichia coli Membranes by Graphene Nanosheets. Nat. Nanotechnol. 2013, 8 (8), 594– 601, DOI: 10.1038/nnano.2013.12564Destructive extraction of phospholipids from Escherichia coli membranes by graphene nanosheetsTu, Yusong; Lv, Min; Xiu, Peng; Huynh, Tien; Zhang, Meng; Castelli, Matteo; Liu, Zengrong; Huang, Qing; Fan, Chunhai; Fang, Haiping; Zhou, RuhongNature Nanotechnology (2013), 8 (8), 594-601CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Understanding how nanomaterials interact with cell membranes is related to how they cause cytotoxicity and is therefore crit. for designing safer biomedical applications. Recently, graphene (a two-dimensional nanomaterial) was shown to have antibacterial activity on Escherichia coli, but its underlying mol. mechanisms remain unknown. Here we show exptl. and theor. that pristine graphene and graphene oxide nanosheets can induce the degrdn. of the inner and outer cell membranes of Escherichia coli, and reduce their viability. TEM shows three rough stages, and mol. dynamics simulations reveal the at. details of the process. Graphene nanosheets can penetrate into and ext. large amts. of phospholipids from the cell membranes because of the strong dispersion interactions between graphene and lipid mols. This destructive extn. offers a novel mechanism for the mol. basis of graphene's cytotoxicity and antibacterial activity.
- 64Mohandas, A.; Deepthi, S.; Biswas, R.; Jayakumar, R. Chitosan Based Metallic Nanocomposite Scaffolds as Antimicrobial Wound Dressings. Bioactive Materials 2018, 3 (3), 267– 277, DOI: 10.1016/j.bioactmat.2017.11.00365Chitosan based metallic nanocomposite scaffolds as antimicrobial wound dressingsMohandas Annapoorna; Deepthi S; Biswas Raja; Jayakumar RBioactive materials (2018), 3 (3), 267-277 ISSN:.Chitosan based nanocomposite scaffolds have attracted wider applications in medicine, in the area of drug delivery, tissue engineering and wound healing. Chitosan matrix incorporated with nanometallic components has immense potential in the area of wound dressings due to its antimicrobial properties. This review focuses on the different combinations of Chitosan metal nanocomposites such as Chitosan/nAg, Chitosan/nAu, Chitosan/nCu, Chitosan/nZnO and Chitosan/nTiO2 towards enhancement of healing or infection control with special reference to the antimicrobial mechanism of action and toxicity.
- 65Zarrintaj, P.; Moghaddam, A. S.; Manouchehri, S.; Atoufi, Z.; Amiri, A.; Amirkhani, M. A.; Nilforoushzadeh, M. A.; Saeb, M. R.; Hamblin, M. R.; Mozafari, M. Can Regenerative Medicine and Nanotechnology Combine to Heal Wounds? The Search for the Ideal Wound Dressing. Nanomedicine 2017, 12 (19), 2403– 2422, DOI: 10.2217/nnm-2017-017366Can regenerative medicine and nanotechnology combine to heal wounds? The search for the ideal wound dressingZarrintaj, Payam; Moghaddam, Abolfazl Salehi; Manouchehri, Saeed; Atoufi, Zhaleh; Amiri, Anahita; Amirkhani, Mohammad Amir; Nilforoushzadeh, Mohammad Ali; Saeb, Mohammad Reza; Hamblin, Michael R.; Mozafari, MasoudNanomedicine (London, United Kingdom) (2017), 12 (19), 2403-2422CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)A review. Skin is the outermost covering of the human body and at the same time the largest organ comprising 15% of body wt. and 2 m2 surface area. Skin plays a key role as a barrier against the outer environment depending on its thickness, color and structure, which differ from one site to another. The four major types of problematic wounds include ulcers (diabetic, venous, pressure) and burn wounds. Developing novel dressings helps us to improve the wound healing process in difficult patients. Recent advances in regenerative medicine and nanotechnol. are revolutionizing the field of wound healing. Antimicrobial activity, exogenous cell therapy, growth factor delivery, biodegradable and biocompatible matrix construction, all play a role in hi-tech dressing design. In the present review, we discuss how the principles of regenerative medicine and nanotechnol. can be combined in innovative wound dressings.
- 66Han, G.; Ceilley, R. Chronic Wound Healing: A Review of Current Management and Treatments. Adv. Ther. 2017, 34 (3), 599– 610, DOI: 10.1007/s12325-017-0478-y67Chronic Wound Healing: A Review of Current Management and TreatmentsHan George; Ceilley RogerAdvances in therapy (2017), 34 (3), 599-610 ISSN:.Wound healing is a complex, highly regulated process that is critical in maintaining the barrier function of skin. With numerous disease processes, the cascade of events involved in wound healing can be affected, resulting in chronic, non-healing wounds that subject the patient to significant discomfort and distress while draining the medical system of an enormous amount of resources. The healing of a superficial wound requires many factors to work in concert, and wound dressings and treatments have evolved considerably to address possible barriers to wound healing, ranging from infection to hypoxia. Even optimally, wound tissue never reaches its pre-injured strength and multiple aberrant healing states can result in chronic non-healing wounds. This article will review wound healing physiology and discuss current approaches for treating a wound.
- 67Li, J.; Zhai, D.; Lv, F.; Yu, Q.; Ma, H.; Yin, J.; Yi, Z.; Liu, M.; Chang, J.; Wu, C. Preparation of Copper-Containing Bioactive Glass/Eggshell Membrane Nanocomposites for Improving Angiogenesis, Antibacterial Activity and Wound Healing. Acta Biomater. 2016, 36, 254– 266, DOI: 10.1016/j.actbio.2016.03.01168Preparation of copper-containing bioactive glass/eggshell membrane nanocomposites for improving angiogenesis, antibacterial activity and wound healingLi, Jinyan; Zhai, Dong; Lv, Fang; Yu, Qingqing; Ma, Hongshi; Yin, Jinbo; Yi, Zhengfang; Liu, Mingyao; Chang, Jiang; Wu, ChengtieActa Biomaterialia (2016), 36 (), 254-266CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)Effectively stimulating angiogenesis and avoiding wound infection are great challenges in wound care management. Designing new healing dressings with requisite angiogenic capacity and antibacterial performance is of particular significance. In order to achieve this aim, we prepd. a copper (Cu)-contg. bioactive glass nanocoating (40-50 nm) with uniform nanostructure on natural eggshell membrane (Cu-BG/ESM) by the pulsed laser deposition (PLD) technique. The surface physicochem. properties including hydrophilicity and hardness of ESM were significantly improved after depositing Cu-BG nanocoatings. Meanwhile, 5Cu-BG/ESM films contg. 5 mol% Cu stimulated proangiogenesis by improving vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α protein secretion as well as angiogenesis-related gene expression (VEGF, HIF-1α, VEGF receptor 2 (KDR) and endothelial nitric oxide (eNos)) of human umbilical vein endothelial cells (HUVECs). When used to treat full-thickness skin defects in mice, 5Cu-BG/ESM films enhanced the healing quality as confirmed by the significantly improved angiogenesis (as indicated by CD31 expression) and formation of continuous and uniform epidermis layer in vivo. Furthermore, 5Cu-BG/ESM films could maintain a sustained release of Cu2+ ions and distinctly inhibited the viability of bacteria (Escherichia coli). The results indicate that Cu2+ ions released from Cu-BG/ESM nanocomposite films play an important role for improving both angiogenesis and antibacterial activity and the prepd. nanocomposite films combined Cu-contg. BG nanocoatings with ESM are a promising biomaterial for wound healing application. Designing new healing dressings with requisite angiogenic capacity and antibacterial performance is of particular significance in wound care management. In our study, we successfully prepd. copper-contg. bioactive glass/eggshell membrane (Cu-BG/ESM) nanocomposites with uniform bioactive glass nanocoatings by using pulsed laser deposition (PLD) technol. Due to the deposited Cu-BG nanocoatings on the surface of ESM, Cu-BG/ESM nanocomposites possessed significantly improved physicochem. and biol. properties, including surface hydrophilicity, hardness, antibacterial ability, angiogenesis rate in vitro and wound healing quality in vivo as compared to pure ESM and BG/ESM films. Our study showed that prepd. nanocoatings on Cu-BG/ESM nanocomposites offer a beneficial carrier for sustained release of Cu2+ ions which played a key role for improving both angiogenesis and antibacterial activity. The prepd. nanocomposites combined Cu-contg. BG nanocoatings with ESM are a promising biomaterial for wound healing application.
- 68Balcucho, J.; Narváez, D. M.; Castro-Mayorga, J. L. Antimicrobial and Biocompatible Polycaprolactone and Copper Oxide Nanoparticle Wound Dressings against Methicillin-Resistant Staphylococcus aureus. Nanomaterials 2020, 10 (9), 1692, DOI: 10.3390/nano1009169269Antimicrobial and biocompatible polycaprolactone and copper oxide nanoparticlewound dressings against methicillin-resistant Staphylococcus aureusBalcucho, Jennifer; Narvaez, Diana M.; Castro-Mayorga, Jinneth LorenaNanomaterials (2020), 10 (9), 1692CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)One of the major health problems linked to methicillin-resistant Staphylococcus aureus (MRSA) is severe diabetic foot ulcers (DFU), which are assocd. with hospital-acquired infections, lower limb amputations and emerging resistance to the current antibiotics. As an alternative, this work aims to develop a biodegradable and biocompatible material with antimicrobial capacity to prevent DFU. This was achieved by producing active polymeric films with metallic nanoparticles dispersed through a polycaprolactone (PCL) dressing. First, the antimicrobial activity of copper oxide nanoparticles (CuONPs) was tested by the microdilution method, selecting the lowest concn. that has an inhibitory effect on MRSA. Then, active PCL films were prepd. and characterized in terms of their physicochem. properties, antimicrobial performance, cytotoxicity, genotoxicity and hemocompatibility. Active films had chem. and thermal properties like the ones without the antimicrobial agents, which was confirmed through FTIR, Thermogravimetric Anal. (TGA) and Differential Scanning Calorimetry (DSC) anal. In relation to antimicrobial activity, active PCL films inhibited MRSA growth when treated with CuONPs at a concn. of 0.07% (wt./wt.). After exposure to the active film exts., human foreskin fibroblast cells (ATCC SCRC1041) (HFF-1) exhibited a cell viability av. above 80% for all treatments and no DNA damage was found. Finally, PCL films with 0.07% (wt./wt.) CuONPs proved to be hemocompatible, and none of the films evaluated had red blood cell breakage greater than 5%, being within the acceptable limits established by the International Organization for Standardization ISO 10993-4:2002.
- 69Tang, L.; Zhu, L.; Tang, F.; Yao, C.; Wang, J.; Li, L. Mild Synthesis of Copper Nanoparticles with Enhanced Oxidative Stability and Their Application in Antibacterial Films. Langmuir 2018, 34 (48), 14570– 14576, DOI: 10.1021/acs.langmuir.8b0247070Mild Synthesis of Copper Nanoparticles with Enhanced Oxidative Stability and Their Application in Antibacterial FilmsTang, Liangzhen; Zhu, Li; Tang, Fu; Yao, Chuang; Wang, Jie; Li, LidongLangmuir (2018), 34 (48), 14570-14576CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)Copper nanoparticles possess unique phys. and chem. properties; however, their application is often restricted, owing to their tendency to oxidize. In this work, we prepd. copper nanoparticles with enhanced oxidative stability via a simple and low-cost method, where a modified starch was used as an environmentally friendly reducing agent and biocompatible polyethylenimine was used as a stabilizer. The prepd. copper nanoparticles could be stored in air for at least 6 mo without any oxidn. in a dried state. Interestingly, our synthesis could even be performed at room temp. with a longer reaction time. We used various characterization methods to study the reaction mechanism. The prepd. copper nanoparticles were further uniformly doped into an agar film, and this composite showed excellent bacterial killing efficiency, owing to the antibacterial properties of the copper nanoparticles. Our composite film shows potential for various clin. applications, such as wound dressing materials.
- 70Jayaramudu, T.; Varaprasad, K.; Reddy, K. K.; Pyarasani, R. D.; Akbari-Fakhrabadi, A.; Amalraj, J. Chitosan-Pluronic Based Cu Nanocomposite Hydrogels for Prototype Antimicrobial Applications. Int. J. Biol. Macromol. 2020, 143, 825– 832, DOI: 10.1016/j.ijbiomac.2019.09.14372Chitosan-pluronic based Cu nanocomposite hydrogels for prototype antimicrobial applicationsJayaramudu, Tippabattini; Varaprasad, Kokkarachedu; Reddy, K. Koteshwara; Pyarasani, Radha D.; Akbari-Fakhrabadi, A.; Amalraj, JohnInternational Journal of Biological Macromolecules (2020), 143 (), 825-832CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)Copper nanoparticles were synthesized via pptn. technique using the pseudonatural cationic chitosan biopolymer as a stabilizing agent. The nanoparticles developed were successfully incorporated into the 1:1 ratio of blended chitosan: pluronic F127 polymer soln. and made their nanocomposite hydrogels by soln. casting method. The formed copper-based nanocomposite hydrogels were characterized by using Fourier transform IR spectroscopy, thermogravimetric anal., X-ray diffraction, SEM-energy dispersive spectroscopy and transmission electron microscopy studies. The antimicrobial activity of the fabricated nanocomposite hydrogels was tested via an inhibition zone process against both E. coli (gram-neg.) and S. aureus (gram-pos.) bacteria. The results conveyed that the copper-embedded chitosan-pluronic\ F127 nanocomposite hydrogels can be used effectively for antimicrobial applications as well as for wound care applications.
- 71Hanafy, N.; Leporatti, S.; El-Kemary, M. Mucoadhesive Hydrogel Nanoparticles as Smart Biomedical Drug Delivery System. Appl. Sci. 2019, 9 (5), 825, DOI: 10.3390/app905082573Mucoadhesive hydrogel nanoparticles as smart biomedical drug delivery systemHanafy, Nemany A. N.; Leporatti, Stefano; El-Kemary, Maged A.Applied Sciences (2019), 9 (5), 825CODEN: ASPCC7; ISSN:2076-3417. (MDPI AG)Hydrogels are widely used materials which have many medical applications. Their ability to absorb aq. solns. and biol. fluids gives them innovative characterizations resulting in increased compatibility with biol. activity. In this sense, they are used extensively for encapsulation of several targets such as biomols., viruses, bacteria, and mammalian cells. Indeed, many methods have been published which are used in hydrogel formulation and biomedical encapsulations involving several cross-linkers. This system is still rich with the potential of undiscovered features. The physicochem. properties of polymers, distinguished by their interactions with biol. systems into mucoadhesive, gastro-adhesive, and stimuli responsive polymers. Hydrogel systems may be assembled as tablets, patches, gels, ointments, and films. Their potential to be co-formulated as nanoparticles extends the limits of their assembly and application. In this review, mucoadhesive nanoparticles and their importance for biomedical applications are highlighted with a focus on mechanisms of overcoming mucosal resistance.
- 72Vuković, J. S.; Babić, M. M.; Antić, K. M.; Miljković, M. G.; Perić-Grujić, A. A.; Filipović, J. M.; Tomić, S. L. A High Efficacy Antimicrobial Acrylate Based Hydrogels with Incorporated Copper for Wound Healing Application. Mater. Chem. Phys. 2015, 164, 51– 62, DOI: 10.1016/j.matchemphys.2015.08.02274A high efficacy antimicrobial acrylate based hydrogels with incorporated copper for wound healing applicationVukovic, Jovana S.; Babic, Marija M.; Antic, Katarina M.; Miljkovic, Miona G.; Peric-Grujic, Aleksandra A.; Filipovic, Jovanka M.; Tomic, Simonida Lj.Materials Chemistry and Physics (2015), 164 (), 51-62CODEN: MCHPDR; ISSN:0254-0584. (Elsevier B.V.)In this study, three series of hydrogels based on 2-hydroxyethyl acrylate and itaconic acid, unloaded, with incorporated copper(II) ions and reduced copper, were successfully prepd., characterized and evaluated as novel wound healing materials. Fourier transform IR spectroscopy (FTIR) confirmed the expected structure of obtained hydrogels. SEM (SEM) revealed porous morphol. of unloaded hydrogels, and the morphol. modifications in case of loaded hydrogels. Thermal characteristics were examd. by differential scanning calorimetry (DSC) and the glass transition temps. were obsd. in range of 12-50 °C. Swelling study was conducted in wide range of pHs at 37 °C, confirming pH sensitive behavior for all three series of hydrogels. The in vitro copper release was investigated and the exptl. data were analyzed using several models in order to elucidate the transport mechanism. The antimicrobial assay revealed excellent antimicrobial activity, over 99% against Escherichia coli, Staphylococcus aureus and Candida albicans, as well as good correlation with the copper release expts. In accordance with potential application, water vapor transmission rate, oxygen penetration, dispersion characteristics, fluid retention were obsd. and the suitability of the hydrogels for wound healing application was discussed.
- 73Villanueva, M. E.; Diez, A. M. D. R.; González, J. A.; Pérez, C. J.; Orrego, M.; Piehl, L.; Teves, S.; Copello, G. J. Antimicrobial Activity of Starch Hydrogel Incorporated with Copper Nanoparticles. ACS Appl. Mater. Interfaces 2016, 8 (25), 16280– 16288, DOI: 10.1021/acsami.6b0295575Antimicrobial Activity of Starch Hydrogel Incorporated with Copper NanoparticlesVillanueva, Maria Emilia; Diez, Ana Maria del Rosario; Gonzalez, Joaquin Antonio; Perez, Claudio Javier; Orrego, Manuel; Piehl, Lidia; Teves, Sergio; Copello, Guillermo JavierACS Applied Materials & Interfaces (2016), 8 (25), 16280-16288CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)In order to obtain an antimicrobial gel, a starch-based hydrogel reinforced with silica-coated copper nanoparticles (Cu NPs) was developed. Cu NPs were synthesized by use of a copper salt and hydrazine as a reducing agent. In order to enhance Cu NP stability over time, they were synthesized in a starch medium followed by a silica coating. The starch hydrogel was prepd. by use of urea and water as plasticizers and it was treated with different concns. of silica-coated copper nanoparticles (Si-Cu NPs). The obtained materials were characterized by Fourier transform IR (FT-IR) spectroscopy, ESR (EPR) spectroscopy, SEM (SEM), and rheometry. FT-IR and EPR spectra were used for characterization of Cu NPs and Si-Cu NPs, confirming that a starch cap was formed around the Cu NP and demonstrating the stability of the copper nanoparticle after the silica coating step. SEM images showed Cu NP, Si-Cu NP, and hydrogel morphol. The particle size was polydisperse and the structure of the gels changed along with particle concn. Increased NP content led to larger pores in starch structure. These results were in accordance with the rheol. behavior, where reinforcement by the Si-Cu NP was seen. Antimicrobial activity was evaluated against Gram-neg. (Escherichia coli) and Gram-pos. (Staphylococcus aureus) bacterial species. The hydrogels were demonstrated to maintain antimicrobial activity for at least four cycles of use. A dermal acute toxicity test showed that the material could be scored as slightly irritant, proving its biocompatibility. With these advantages, it is believed that the designed Si-Cu NP loaded hydrogel may show high potential for applications in various clin. fields, such as wound dressings and fillers.
- 74Qiu, H.; Pu, F.; Liu, Z.; Liu, X.; Dong, K.; Liu, C.; Ren, J.; Qu, X. Hydrogel-Based Artificial Enzyme for Combating Bacteria and Accelerating Wound Healing. Nano Res. 2020, 13 (2), 496– 502, DOI: 10.1007/s12274-020-2636-976Hydrogel-based artificial enzyme for combating bacteria and accelerating wound healingQiu, Hao; Pu, Fang; Liu, Zhengwei; Liu, Xuemeng; Dong, Kai; Liu, Chaoqun; Ren, Jinsong; Qu, XiaogangNano Research (2020), 13 (2), 496-502CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)Artificial enzymes have provided great antimicrobial activity to combat wound infection. However, the lack of tissue repair capability compromised their treatment effect. Therefore, development of novel artificial enzyme concurrently with the excellent antibacterial activity and the property of promoting wound healing are required. Here, we demonstrated the hydrogel-based artificial enzyme composed of copper and amino acids possessed intrinsic peroxidase-like catalytic activity, which could combat wound pathogen effectively and accelerate wound healing by stimulating angiogenesis and collagen deposition. Furthermore, the system possesses good biocompatibility for practical application. The synergic effect of the hydrogel-based artificial enzyme promises the system as a new paradigm in bacteria-infected wound healing therapy.
- 75Cady, N. C.; Behnke, J. L.; Strickland, A. D. Copper-Based Nanostructured Coatings on Natural Cellulose: Nanocomposites Exhibiting Rapid and Efficient Inhibition of a Multi-Drug Resistant Wound Pathogen, A. Baumannii, and Mammalian Cell Biocompatibility in Vitro. Adv. Funct. Mater. 2011, 21 (13), 2506– 2514, DOI: 10.1002/adfm.20110012377Copper-Based Nanostructured Coatings on Natural Cellulose: Nanocomposites Exhibiting Rapid and Efficient Inhibition of a Multi-Drug Resistant Wound Pathogen, A. baumannii, and Mammalian Cell Biocompatibility In VitroCady, Nathaniel C.; Behnke, Jason L.; Strickland, Aaron D.Advanced Functional Materials (2011), 21 (13), 2506-2514CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)This paper describes a layer-by-layer (LBL) electrostatic self-assembly process for fabricating highly efficient antimicrobial nanocoatings on a natural cellulose substrate. The composite materials comprise a chem. modified cotton substrate and a layer of sub-5 nm copper-based nanoparticles. The LBL process involves a chem. preconditioning step to impart high neg. surface charge on the cotton substrate for chelation controlled binding of cupric ions (Cu2+), followed by chem. redn. to yield nanostructured coatings on cotton fibers. These model wound dressings exhibit rapid and efficient killing of a multidrug resistant bacterial wound pathogen, A. baumannii, where an 8-log redn. in bacterial growth can be achieved in as little as 10 min of contact. Comparative silver-based nanocoated wound dressings-a more conventional antimicrobial composite material-exhibit much lower antimicrobial efficiencies; a 5-log redn. in A. baumannii growth is possible after 24 h exposure times to silver nanoparticle-coated cotton substrates. The copper nanoparticle-cotton composites described herein also resist leaching of copper species in the presence of buffer, and exhibit an order of magnitude higher killing efficiency using 20 times less total metal when compared to tests using sol. Cu2+. Together these data suggest that copper-based nanoparticle-coated cotton materials have facile antimicrobial properties in the presence of A. baumannii through a process that may be assocd. with contact killing, and not simply due to enhanced release of metal ion. The biocompatibility of these copper-cotton composites toward embryonic fibroblast stem cells in vitro suggests their potential as a new paradigm in metal-based wound care and combating pathogenic bacterial infections.
- 76Torres, F. G.; Arroyo, J. J.; Troncoso, O. P. Bacterial Cellulose Nanocomposites: An All-Nano Type of Material. Mater. Sci. Eng., C 2019, 98, 1277– 1293, DOI: 10.1016/j.msec.2019.01.06478Bacterial cellulose nanocomposites: An all-nano type of materialTorres, F. G.; Arroyo, J. J.; Troncoso, O. P.Materials Science & Engineering, C: Materials for Biological Applications (2019), 98 (), 1277-1293CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)A review. Bacterial cellulose (BC) is a fascinating polymer with a three-dimensional structure formed by nanofibers of pure cellulose, synthesized by some bacteria and organized as a coherent network. Its biocompatibility and remarkable mech. properties have promoted scientific interest for its use in a variety of applications including biomedical, elec., among others. However, it is the possibility of incorporating nanosized materials into the coherent 3-D network structure displayed by BC what has propelled multiple investigations on the development of BC nanocomposites for different applications. Here we report the different methods and techniques used so far for the BC nanocomposites prodn. We have focused on the processing techniques that allow the incorporation of functional nanoreinforcements, nanofillers and addnl. phases without disturbing the original network structure, leading to the formation of nanomaterials. Processing methods, resulting structure-property relationships and potential applications of these novel nanocomposites are discussed and showcased as a fair example of integrated design and manuf. of materials.
- 77Portela, R.; Leal, C. R.; Almeida, P. L.; Sobral, R. G. Bacterial Cellulose: A Versatile Biopolymer for Wound Dressing Applications. Microb. Biotechnol. 2019, 12 (4), 586– 610, DOI: 10.1111/1751-7915.1339279Bacterial cellulose: a versatile biopolymer for wound dressing applicationsPortela, Raquel; Leal, Catarina R.; Almeida, Pedro L.; Sobral, Rita G.Microbial Biotechnology (2019), 12 (4), 586-610CODEN: MBIIB2; ISSN:1751-7915. (Wiley-Blackwell)A review. Summary : Although several therapeutic approaches are available for wound and burn treatment and much progress has been made in this area, room for improvement still exists, driven by the urgent need of better strategies to accelerate wound healing and recovery, mostly for cases of severe burned patients. Bacterial cellulose (BC) is a biopolymer produced by bacteria with several advantages over vegetal cellulose, such as purity, high porosity, permeability to liq. and gases, elevated water uptake capacity and mech. robustness. Besides its biocompatibility, BC can be modified in order to acquire antibacterial response and possible local drug delivery features. Due to its intrinsic versatility, BC is the perfect example of a biotechnol. response to a clin. problem. In this review, we assess the BC main features and emphasis is given to a specific biomedical application: wound dressings. The prodn. process and the phys.-chem. properties that entitle this material to be used as wound dressing namely for burn healing are highlighted. An overview of the most common BC composites and their enhanced properties, in particular phys. and biol., is provided, including the different prodn. processes. A particular focus is given to the biochem. and genetic manipulation of BC. A summary of the current marketed BC-based wound dressing products is presented, and finally, future perspectives for the usage of BC as wound dressing are foreseen.
- 78Gutierrez, E.; Burdiles, P. A.; Quero, F.; Palma, P.; Olate-Moya, F.; Palza, H. 3D Printing of Antimicrobial Alginate/Bacterial-Cellulose Composite Hydrogels by Incorporating Copper Nanostructures. ACS Biomater. Sci. Eng. 2019, 5 (11), 6290– 6299, DOI: 10.1021/acsbiomaterials.9b01048803D Printing of Antimicrobial Alginate/Bacterial-Cellulose Composite Hydrogels by Incorporating Copper NanostructuresGutierrez, Elena; Burdiles, Patricio A.; Quero, Franck; Palma, Patricia; Olate-Moya, Felipe; Palza, HumbertoACS Biomaterials Science & Engineering (2019), 5 (11), 6290-6299CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)Novel antimicrobial 3D-printed alginate/bacterial-cellulose hydrogels with in situ-synthesized copper nanostructures were developed having improved printability. Prior to 3D printing, two methods were tested for the development of the alginate hydrogels: (a) ionic crosslinking with calcium ions followed by ion exchange with copper ions (method A) and (b) ionic crosslinking with copper ions (method B). A soln. contg. sodium borohydride, used as a reducing agent, was subsequently added to the hydrogels, producing in situ clusters of copper nanoparticles embedded in the alginate hydrogel matrix. The method used and concns. of copper and the reducing agent were found to affect the stability of the alginate/copper hydrogels, with method A producing more stable materials. By increasing the alginate concn. from 1 to 4 wt % and by using method A, alginate/bacterial-cellulose/copper hydrogel structures were 3D-printed having excellent printability as compared with pure alginate hydrogels. It is noteworthy that after redn. with sodium borohydride, the 3D structures presented antimicrobial behavior against Escherichia coli and Staphylococcus aureus strains. Our results introduce a simple route for the prodn. of alginate/cellulose inks with improved behavior toward antimicrobial 3D-printed materials.
- 79Chowdhury, M. N. K.; Beg, M. D. H.; Khan, M. R.; Mina, M. F. Synthesis of Copper Nanoparticles and Their Antimicrobial Performances in Natural Fibres. Mater. Lett. 2013, 98, 26– 29, DOI: 10.1016/j.matlet.2013.02.02481Synthesis of copper nanoparticles and their antimicrobial performances in natural fibresChowdhury, M. N. K.; Beg, M. D. H.; Khan, Maksudur R.; Mina, M. F.Materials Letters (2013), 98 (), 26-29CODEN: MLETDJ; ISSN:0167-577X. (Elsevier B.V.)Copper nanoparticles (CuNPs) were synthesized at ambient atm. condition by the chem. redn. method. The redn. of the soln. of copper chloride salt in the polyvinyl alc. system was done by sodium borohydride soln. The UV-visible spectroscopy, Fourier transformed IR spectroscopy, transmission electron microscopy and X-ray diffraction studies were employed to analyze the formations and sizes of nanoparticles. The av. size of CuNPs was measured to be 3 nm. The synthesized CuNPs were impregnated in natural fibers and their antimicrobial performances were assessed against both the Gram-pos. and Gram-neg. bacteria, showing more antibacterial activity in Escherichia coli than Staphylococcus aureus along with ∼7% antifungal activity.
- 80Valencia, L.; Kumar, S.; Nomena, E. M.; Salazar-Alvarez, G.; Mathew, A. P. In-Situ Growth of Metal Oxide Nanoparticles on Cellulose Nanofibrils for Dye Removal and Antimicrobial Applications. ACS Appl. Nano Mater. 2020, 3 (7), 7172– 7181, DOI: 10.1021/acsanm.0c0151182In-Situ Growth of Metal Oxide Nanoparticles on Cellulose Nanofibrils for Dye Removal and Antimicrobial ApplicationsValencia, Luis; Kumar, Sugam; Nomena, Emma M.; Salazar-Alvarez, German; Mathew, Aji P.ACS Applied Nano Materials (2020), 3 (7), 7172-7181CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)Nanocellulose is known to act as a platform for the in-situ formation of metal oxide nanoparticles, where the multiple components of the resultant hybrids act synergistically toward specific applications. However, typical mineralization reactions require hydrothermal conditions or addn. of further reducing agents. Herein, we demonstrate that carboxylated cellulose nanofibril-based films can spontaneously grow functional metal oxide nanoparticles during the adsorption of heavy metal ions from water, without the need of any further chems. or temp. Despite the apparent universality of this behavior with different metal ions, this work focuses on studying the in-situ formation of copper oxide nanoparticles on TOCNF films as well as the resultant hybrid films with improved functionality toward dye removal from water and antimicrobial activity. Using a combination of cutting-edge techniques (e.g., in-situ SAXS and QCMD) to systematically follow the nanoparticle formation on the nanocellulosic films in real time, we suggest a plausible mechanism of assembly. Our results confirm that carboxylated cellulose nanofibril films act as universal substrate for the formation of metal oxide nanoparticles, and thus hybrid nanomaterials, during metal ion adsorption processes. This phenomenon enables the upcycling of nanocellulosic materials through multistage applications, thus increasing its sustainability and efficiency in terms of an optimal use of resources.
- 81Shahidi, S.; Rashidian, M.; Dorranian, D. Preparation of Antibacterial Textile Using Laser Ablation Method. Opt. Laser Technol. 2018, 99, 145– 153, DOI: 10.1016/j.optlastec.2017.08.02583Preparation of antibacterial textile using laser ablation methodShahidi, Sheila; Rashidian, M.; Dorranian, D.Optics & Laser Technology (2018), 99 (), 145-153CODEN: OLTCAS; ISSN:0030-3992. (Elsevier Ltd.)A facile in situ laser ablation synthesis of copper nanoparticles on cotton fabric is reported in this paper. This synthetic method is a laser ablation based fabrication of Cu nanoparticles on cotton fabric for improved performance and antibacterial activity. The treated cotton fabric was characterized using SEM, energy dispersive X-ray spectroscopy, UV-Visible spectroscopic techniques and antibacterial counting test. Very good antibacterial behavior of treated fabrics achieved. This fabric can be used as medical and industrial textiles.
- 82Sathiyavimal, S.; Vasantharaj, S.; Bharathi, D.; Saravanan, M.; Manikandan, E.; Kumar, S. S.; Pugazhendhi, A. Biogenesis of Copper Oxide Nanoparticles (CuONPs) Using Sida Acuta and Their Incorporation over Cotton Fabrics to Prevent the Pathogenicity of Gram Negative and Gram Positive Bacteria. J. Photochem. Photobiol., B 2018, 188, 126– 134, DOI: 10.1016/j.jphotobiol.2018.09.01484Biogenesis of copper oxide nanoparticles (CuONPs) using Sida acuta and their incorporation over cotton fabrics to prevent the pathogenicity of Gram negative and Gram positive bacteriaSathiyavimal, Selvam; Vasantharaj, Seerangaraj; Bharathi, Devaraj; Saravanan, Mythili; Manikandan, Elayaperumal; Kumar, Smita S.; Pugazhendhi, ArivalaganJournal of Photochemistry and Photobiology, B: Biology (2018), 188 (), 126-134CODEN: JPPBEG; ISSN:1011-1344. (Elsevier B.V.)Textile industry is a major sector providing global financial and employment support to different countries of the world. The major problems of the textile industry are dirt and microbial contaminants affecting the quality of cotton fabrics. Recently, nanoparticles such as silver, chitosan, silicon dioxide, titanium dioxide and zinc oxide have gained attraction in textile industries to avoid the contamination of fabrics through microbes. The necessity to develop an ecofriendly, efficient and cost effective method for the synthesis of nanoparticles is under the radar. Plant exts. serve as potential reducing and coating agents due to the presence of bioactive mols. such as phenols, lipids, carbohydrates, enzymes, protein mols. etc., which endow effective antimicrobial activity to the nanoparticles. In the present study, biol. synthesis of Copper oxide nanoparticles (CuONPs) was performed using S. acuta leaf ext. CuONPs were synthesized and characterized using UV-vis, FTIR, SEM and TEM analyses. The antimicrobial property of CuONPs was tested against Gram neg. (Escherichia coli and Proteus vulgaris) and Gram pos. (Staphylococcus aureus) pathogens, which showed zones of inhibition at different concns. As the final part of the study, CuONPs were coated over cotton fabrics showing longer stability, which prevented the growth of infectious pathogens. Apart from the antimicrobial activity, CuONPs synthesized using S. acuta possessed effective photocatalytic activity against com. dyes.
- 83Marković, D.; Vasiljević, J.; Ašanin, J.; Ilic-Tomic, T.; Tomšič, B.; Jokić, B.; Mitrić, M.; Simončič, B.; Mišić, D.; Radetić, M. The Influence of Coating with Aminopropyl Triethoxysilane and CuO/Cu2O Nanoparticles on Antimicrobial Activity of Cotton Fabrics under Dark Conditions. J. Appl. Polym. Sci. 2020, 137 (40), 49194, DOI: 10.1002/app.4919485The influence of coating with aminopropyl triethoxysilane and CuO/Cu2O nanoparticles on antimicrobial activity of cotton fabrics under dark conditionsMarkovic, Darka; Vasiljevic, Jelena; Asanin, Jelena; Ilic-Tomic, Tatjana; Tomsic, Brigita; Jokic, Bojan; Mitric, Miodrag; Simoncic, Barbara; Misic, Dusan; Radetic, MajaJournal of Applied Polymer Science (2020), 137 (40), 49194CODEN: JAPNAB; ISSN:0021-8995. (John Wiley & Sons, Inc.)A novel impregnation process for the fabrication of cotton nanocomposite with strong antimicrobial activity against antibiotics-resistant bacteria and yeast was developed. The impregnation process includes the sol-gel treatment of fabric with (3-aminopropyl)triethoxysilane in the first step, and synthesis of the CuO/Cu2O nanoparticles (NPs) on the fabric surface in the second step. The in situ synthesis of the CuO/Cu2O NPs was based on the adsorption of Cu2+-ions by the introduced amino groups of the sol-gel coating. The adsorbed Cu2+-ions are subsequently reduced in the alk. soln. of NaBH4. X-ray diffraction measurements confirmed the formation of CuO/Cu2O NPs. SEM and at. absorption spectrometry analyses indicate that the particle size, agglomeration, and amts. of synthesized NPs were highly affected by the initial concn. of CuSO4 soln. The toxicity of nanocomposites to human keratinocytes (HaCaT) and antimicrobial activity against Gram-neg. Escherichia coli ATCC 25922, E. coli ATCC BAA 2469, and Klebsiella pneumoniae ATCC BAA 2146, and Gram-pos. bacteria Staphylococcus aureus ATCC 25923, S. aureus ATCC 43300 and yeast Candida albicans ATCC 24433 strongly depended on the copper content. In addn. to excellent antimicrobial activity, controlled release of Cu2+-ions from the fabrics into physiol. saline soln. was obtained.
- 84Mapanao, A. K.; Santi, M.; Voliani, V. Combined chemo-photothermal treatment of 3D head and neck squamous cell carcinomas by ultrasmall-in-nano gold architectures. J. Colloid Interface Sci. 2021, 582, 1003– 1011, DOI: 10.1016/j.jcis.2020.08.0598600Combined chemo-photothermal treatment of three-dimensional head and neck squamous cell carcinomas by gold nano-architecturesMapanao, Ana Katrina; Santi, Melissa; Voliani, ValerioJournal of Colloid and Interface Science (2021), 582 (Part_B), 1003-1011CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)Synergistic combined treatments are currently practiced in clinics for the management of several neoplasms. While surgery, radiotherapy, and chemotherapy remain as the stds. of care for monomodal and co-treatments, emerging modalities like hyperthermia (HT) demonstrate promising features as (neo)adjuvant, particularly for recurrent cancers. However, the clin. relevance of HT is still debated due to a no. of challenges, such as tumor specific temp. increase, uneven heating of the target, and the lack of agents that concurrently execute HT in combination with radio- and/or chemotherapy. Here, the application of non-persistent ultrasmall-in-nano gold architectures for synergistic chemo-photothermal treatment of head and neck squamous cell carcinomas (HNSCCs) is presented. The nano-architectures are composed of excretable narrow near-IR (NIR)-absorbing gold ultrasmall nanoparticles and an endogenously double controlled cisplatin prodrug. The efficiency of the nano-architectures is evaluated on three-dimensional (3D) models of HNSCCs with pos. or neg. human papillomavirus (HPV) status. The combined treatment causes a more pronounced antitumor action on HPV-pos. HNSCCs. Overall, the findings demonstrate the potential clin. relevance of translatable noble metal-based synergistic treatments in tumors management.
- 85Cassano, D.; Santi, M.; D’Autilia, F.; Mapanao, A. K.; Luin, S.; Voliani, V. Photothermal effect by NIR-responsive excretable ultrasmall-in-nano architectures. Mater. Horiz. 2019, 6, 531– 537, DOI: 10.1039/C9MH00096H8601Photothermal effect by NIR-responsive excretable ultrasmall-in-nano architecturesCassano, Domenico; Santi, Melissa; D'Autilia, Francesca; Mapanao, Ana Katrina; Luin, Stefano; Voliani, ValerioMaterials Horizons (2019), 6 (3), 531-537CODEN: MHAOBM; ISSN:2051-6355. (Royal Society of Chemistry)Photothermal therapy (PTT) is a promising (co)treatment with translation potentiality in oncol. Nowadays, the plasmonic nanoparticle-mediated photothermal effect (PT) relies on two well established NIR-responsive platforms: gold nanorods and nanoshells. Nonetheless, these nanostructures are affected by: (i) re-shaping after irradn. that prevents multiple PT treatments, and (ii) severe limitations to clin. translation due to metal persistence issues. Furthermore, evaluation of nanoparticle performance is usually accomplished in vitro or in mouse models, reducing the translational potential of the findings. Here, we report both the straightforward prodn. of narrow-NIR-absorbing gold ultrasmall-in-nano architectures (tNAs) and their suitability as platforms for PT upon CW-irradn. at 808 nm. PT efficiency is fully assessed against 2D cell cultures and customized 3D pancreatic adenocarcinoma models.
- 86Li, L.; Rashidi, L. H.; Yao, M.; Ma, L.; Chen, L.; Zhang, J.; Zhang, Y.; Chen, W. CuS Nanoagents for Photodynamic and Photothermal Therapies: Phenomena and Possible Mechanisms. Photodiagn. Photodyn. Ther. 2017, 19, 5– 14, DOI: 10.1016/j.pdpdt.2017.04.00186CuS nanoagents for photodynamic and photothermal therapies: Phenomena and possible mechanismsLi, Lihua; Rashidi, Leila H.; Yao, Mengyu; Ma, Lun; Chen, Lingling; Zhang, Junying; Zhang, Yu; Chen, WeiPhotodiagnosis and Photodynamic Therapy (2017), 19 (), 5-14CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)Photodynamic therapy (PDT) and photothermal therapy (PTT) have been emerging as attractive and promising methods for tumor treatment in clin. approaches. CuS nanoparticles are effective and cost-effective agents for PTT. Recently, it was obsd. that CuS nanoparticles are also excellence candidates for PDT. However, the mechanisms for CuS nanoparticles as PDT agents have never been discussed. The goal here is to explore the killing mechanisms of CuS nanoparticles as PTT and PDT agents. CuS nanoparticles were synthesized by a simple wet chem. method by coating with amphiphilic polymer and examd. for their therapeutic potential on lung adenocarcinoma cell line SPC-A-1 in vitro and in vivo using a murine cancer model. The CuS nanoparticles produce heat as well as reactive oxygen species (ROS) when excited by 808 nm laser and show strong anticancer effects both in vitro and in vivo. The heating effects and release of copper ions from CuS upon heating in the tumor acidic environments are the main mechanisms for the generation of reactive oxygen species which are lethal bullets for cancer destruction. As a dual-function agent for PTT and PDT, CuS nanoparticles are promising phototherapy agents for cancer treatment.
- 87Li, Y.; Lu, W.; Huang, Q.; Li, C.; Chen, W. Copper Sulfide Nanoparticles for Photothermal Ablation of Tumor Cells. Nanomedicine 2010, 5 (8), 1161– 1171, DOI: 10.2217/nnm.10.8587Copper sulfide nanoparticles for photothermal ablation of tumor cellsLi, Yuebin; Lu, Wei; Huang, Qian; Li, Chun; Chen, WeiNanomedicine (London, United Kingdom) (2010), 5 (8), 1161-1171CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Copper sulfide (CuS) nanoparticles were developed as a new type of agent for photothermal ablation of cancer cells. CuS nanoparticles were synthesized by wet chem. and their application in photothermal ablation of tumor cells was tested by irradn. using a near-IR (NIR) laser beam at 808 nm to elevate the temp. of aq. solns. of CuS nanoparticles as a function of exposure time and nanoparticle concn. CuS nanoparticle-mediated photothermal destruction was evaluated using human cervical cancer HeLa cells with respect to laser dose and nanoparticle concn. Their toxicity was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. CuS nanoparticles have an optical absorption band in the NIR range with a max. absorbance at 900 nm. Irradn. by a NIR laser beam at 808 nm resulted in an increase in the temp. of the CuS nanoparticle aq. soln. as a function of exposure time and nanoparticle concn. CuS nanoparticle-induced photothermal destruction of HeLa cells occurred in a laser dose- and nanoparticle concn.-dependent manner, and displayed minimal cytotoxic effects with a profile similar to that of gold nanoparticles. Owing to their unique optical property, small size, low cost of prodn. and low cytotoxicity, CuS nanoparticles are promising new nanomaterials for cancer photothermal ablation therapy.
- 88Borzenkov, M.; Pallavicini, P.; Taglietti, A.; D’Alfonso, L.; Collini, M.; Chirico, G. Photothermally Active Nanoparticles as a Promising Tool for Eliminating Bacteria and Biofilms. Beilstein J. Nanotechnol. 2020, 11, 1134– 1146, DOI: 10.3762/bjnano.11.9888Photothermally active nanoparticles as a promising tool for eliminating bacteria and biofilmsBorzenkov, Mykola; Pallavicini, Piersandro; Taglietti, Angelo; D'Alfonso, Laura; Collini, Maddalena; Chirico, GiuseppeBeilstein Journal of Nanotechnology (2020), 11 (), 1134-1146CODEN: BJNEAH; ISSN:2190-4286. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A review. Bacterial contamination is a severe issue that affects medical devices, hospital tools and surfaces. When microorganisms adhere to a surface (e.g., medical devices or implants) they can develop into a biofilm, thereby becoming more resistant to conventional biocides and disinfectants. Nanoparticles can be used as an antibacterial agent in medical instruments or as a protective coating in implantable devices. In particular, attention is being drawn to photothermally active nanoparticles that are capable of converting absorbed light into heat. These nanoparticles can efficiently eradicate bacteria and biofilms upon light activation (predominantly near the IR to near-IR spectral region) due a rapid and pronounced local temp. increase. By using this approach new, protective, antibacterial surfaces and materials can be developed that can be remotely activated on demand. In this , we summarize the state-of-the art regarding the application of various photothermally active nanoparticles and their corresponding nanocomposites for the light-triggered eradication of bacteria and biofilms.
- 89Wang, X.; Lv, F.; Li, T.; Han, Y.; Yi, Z.; Liu, M.; Chang, J.; Wu, C. Electrospun Micropatterned Nanocomposites Incorporated with Cu2S Nanoflowers for Skin Tumor Therapy and Wound Healing. ACS Nano 2017, 11 (11), 11337– 11349, DOI: 10.1021/acsnano.7b0585889Electrospun Micropatterned Nanocomposites Incorporated with Cu2S Nanoflowers for Skin Tumor Therapy and Wound HealingWang, Xiaocheng; Lv, Fang; Li, Tian; Han, Yiming; Yi, Zhengfang; Liu, Mingyao; Chang, Jiang; Wu, ChengtieACS Nano (2017), 11 (11), 11337-11349CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Surgical excision of skin cancers can hardly remove the tumor tissues completely and simultaneously result in cutaneous defects. To avoid tumor recurrence and heal the tumor-induced wounds, we designed a tissue engineering membrane possessing bifunctions of tumor therapy and skin tissue regeneration. The micropatterned nanocomposite membrane was successfully fabricated by incorporating Cu2S nanoflowers into biopolymer fibers via a modified electrospinning method. With uniformly embedded Cu2S nanoparticles, the membranes exhibited excellent and controllable photothermal performance under near-IR irradn., which resulted in high mortality (>90%) of skin tumor cells and effectively inhibited tumor growth in mice. Moreover, the membranes supported the adhesion, proliferation, and migration of skin cells as well as significantly stimulated angiogenesis and healed full-thickness skin defects in vivo. This proof-of-concept study offers a facile and reliable strategy for localized skin tumor therapy and tissue regeneration using bifunctional tissue engineering biomaterials, showing great promise for tumor-induced wound healing applications.
- 90Zhou, W.; Zi, L.; Cen, Y.; You, C.; Tian, M. Copper Sulfide Nanoparticles-Incorporated Hyaluronic Acid Injectable Hydrogel With Enhanced Angiogenesis to Promote Wound Healing. Front. Bioeng. Biotechnol. 2020, 8 (8), 417, DOI: 10.3389/fbioe.2020.0041790Copper Sulfide Nanoparticles-Incorporated Hyaluronic Acid Injectable Hydrogel With Enhanced Angiogenesis to Promote Wound HealingZhou Wencheng; Zi Liu; You Chao; Tian Meng; Zhou Wencheng; Cen Ying; Tian Meng; Zi Liu; You Chao; Tian Meng; You Chao; Tian MengFrontiers in bioengineering and biotechnology (2020), 8 (), 417 ISSN:2296-4185.Skin wound caused by trauma, inflammation, surgery, or burns remains a great challenge worldwide since there is no effective therapy available to improve its clinical outcomes. Herein, we report a copper sulfide nanoparticles-incorporated hyaluronic acid (CuS/HA) injectable hydrogel with enhanced angiogenesis to promote wound healing. The prepared hydrogel could not only be injected to the wound site but also exhibited good photothermal effect, with temperature increasing to 50°C from room temperature after 10 min of near-infrared light irradiation. The cell culture experiments also showed that the hydrogel has no cytotoxicity. In the rat skin wound model, the hydrogel treated wounds exhibited better healing performances. Masson's trichrome staining suggested that collagen deposition in wounds treated with the hydrogel was significantly higher than other groups. The immunohistochemical staining showed that the hydrogel can effectively upregulate the expression of vascular endothelial growth factor (VEGF) in the wound area at the incipient stage of healing, and the CD 31 immunofluorescence staining confirmed the enhanced angiogenesis of the hydrogel. Taken together, the prepared CuS/HA hydrogel can effectively increase the collagen deposition, upregulate the expression of VEGF, and enhance the angiogenesis, which may contribute to promote wound healing, making it a promising for application in treating skin wound.
- 91Qiao, Y.; Ping, Y.; Zhang, H.; Zhou, B.; Liu, F.; Yu, Y.; Xie, T.; Li, W.; Zhong, D.; Zhang, Y.; Yao, K.; Santos, H. A.; Zhou, M. Laser-Activatable CuS Nanodots to Treat Multidrug-Resistant Bacteria and Release Copper Ion to Accelerate Healing of Infected Chronic Nonhealing Wounds. ACS Appl. Mater. Interfaces 2019, 11 (4), 3809– 3822, DOI: 10.1021/acsami.8b2176691Laser-Activatable CuS Nanodots to Treat Multidrug-Resistant Bacteria and Release Copper Ion to Accelerate Healing of Infected Chronic Nonhealing WoundsQiao, Yue; Ping, Yuan; Zhang, Hongbo; Zhou, Bo; Liu, Fengyong; Yu, Yinhui; Xie, Tingting; Li, Wanli; Zhong, Danni; Zhang, Yuezhou; Yao, Ke; Santos, Helder A.; Zhou, MinACS Applied Materials & Interfaces (2019), 11 (4), 3809-3822CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)Chronic nonhealing wounds have imposed serious challenges in the clin. practice, esp. for the patients infected with multidrug-resistant microbes. Herein, we developed an ultrasmall copper sulfide (covellite) nanodots (CuS NDs) based dual functional nanosystem to cure multidrug-resistant bacteria-infected chronic nonhealing wound. The nanosystem could eradicate multidrug-resistant bacteria and expedite wound healing simultaneously owing to the photothermal effect and remote control of copper-ion release. The antibacterial results indicated that the combination treatment of photothermal CuS NDs with photothermal effect initiated a strong antibacterial effect for drug-resistant pathogens including methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum β-lactamase Escherichia coli both in vitro and in vivo. Meanwhile, the released Cu2+ could promote fibroblast cell migration and endothelial cell angiogenesis, thus accelerating wound-healing effects. In MRSA-infected diabetic mice model, the nanosystem exhibited synergistic wound healing effect of infectious wounds in vivo and demonstrated negligible toxicity and nonspecific damage to major organs. The combination of ultrasmall CuS NDs with photothermal therapy displayed enhanced therapeutic efficacy for chronic nonhealing wound in multidrug-resistant bacterial infections, which may represent a promising class of antibacterial strategy for clin. translation.
- 92Guo, L.; Yan, D. D.; Yang, D.; Li, Y.; Wang, X.; Zalewski, O.; Yan, B.; Lu, W. Combinatorial Photothermal and Immuno Cancer Therapy Using Chitosan-Coated Hollow Copper Sulfide Nanoparticles. ACS Nano 2014, 8 (6), 5670– 5681, DOI: 10.1021/nn500211292Combinatorial Photothermal and Immuno Cancer Therapy Using Chitosan-Coated Hollow Copper Sulfide NanoparticlesGuo, Liangran; Yan, Daisy D.; Yang, Dongfang; Li, Yajuan; Wang, Xiaodong; Zalewski, Olivia; Yan, Bingfang; Lu, WeiACS Nano (2014), 8 (6), 5670-5681CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Near-IR light-responsive inorg. nanoparticles have been shown to enhance the efficacy of cancer photothermal ablation therapy. However, current nanoparticle-mediated photothermal ablation is more effective in treating local cancer at the primary site than metastatic cancer. Here, we report the design of a near-IR light-induced transformative nanoparticle platform that combines photothermal ablation with immunotherapy. The design is based on chitosan-coated hollow CuS nanoparticles that assemble the immunoadjuvants oligodeoxynucleotides contg. the cytosine-guanine (CpG) motifs. Interestingly, these structures break down after laser excitation, reassemble, and transform into polymer complexes that improve tumor retention of the immunotherapy. In this "photothermal immunotherapy" approach, photothermal ablation-induced tumor cell death reduces tumor growth and releases tumor antigens into the surrounding milieu, while the immunoadjuvants potentiate host antitumor immunity. Our results indicated that combined photothermal immunotherapy is more effective than either immunotherapy or photothermal therapy alone against primary treated and distant untreated tumors in a mouse breast cancer model. These hollow CuS nanoparticles are biodegradable and can be eliminated from the body after laser excitation.
- 93Yin, M.; Li, Z.; Ju, E.; Wang, Z.; Dong, K.; Ren, J.; Qu, X. Multifunctional Upconverting Nanoparticles for Near-Infrared Triggered and Synergistic Antibacterial Resistance Therapy. Chem. Commun. 2014, 50 (72), 10488– 10490, DOI: 10.1039/C4CC04584J93Multifunctional upconverting nanoparticles for near-infrared triggered and synergistic antibacterial resistance therapyYin, Meili; Li, Zhenhua; Ju, Enguo; Wang, Zhenzhen; Dong, Kai; Ren, Jinsong; Qu, XiaogangChemical Communications (Cambridge, United Kingdom) (2014), 50 (72), 10488-10490CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)To integrate photodynamic therapy with photothermal therapy for improved multidrug-resistant bacteria therapy, we have constructed a novel multifunctional core/satellite nanostructure by decorating CuS nanoparticles onto the surface of NaYF4:Mn/Yb/Er@photosensitizer doped SiO2. This system exhibited a superior antibacterial activity towards drug-resistant Staphylococcus aureus and Escherichia coli.
- 94Yugandhar, P.; Vasavi, T.; Jayavardhana Rao, Y.; Uma Maheswari Devi, P.; Narasimha, G.; Savithramma, N. Cost Effective, Green Synthesis of Copper Oxide Nanoparticles Using Fruit Extract of Syzygium Alternifolium (Wt.) Walp., Characterization and Evaluation of Antiviral Activity. J. Cluster Sci. 2018, 29 (4), 743– 755, DOI: 10.1007/s10876-018-1395-194Cost Effective, Green Synthesis of Copper Nanoparticles Using Fruit Extract of Syzygium alternifolium (Wt.) Walp., Characterization and Evaluation of Antiviral ActivityYugandhar, Pulicherla; Vasavi, Thirumalanadhuni; Jayavardhana Rao, Yagani; Uma Maheswari Devi, Palempalli; Narasimha, Golla; Savithramma, NataruJournal of Cluster Science (2018), 29 (4), 743-755CODEN: JCSCEB; ISSN:1040-7278. (Springer)The present study was aimed to synthesize copper oxide nanoparticles (CuO NPs) using fruit ext. of Syzygium alternifolium and to evaluate their antiviral activity against Newcastle Disease Virus (NDV). The CuO NPs synthesized, were characterized by employing different spectroscopic and microscopic tools. The peak manifested at 285 nm in UV-Vis anal. confirms the synthesis of CuO NPs. FTIR anal. showed two conspicuous peaks at 3253 and 1461 cm-1 which correspond to O-H stretch of phenols and N-H bond of primary amines of proteins resp. This result confirms their involvement in capping and stabilization of nanoparticles. The DLS and zeta potential studies revealed 61.1 nm av. size and - 49.2 mV of zeta potential (ζ) value. The XRD crystallog. investigations exhibited end-centered monoclinic cryst. nature nanoparticles with 17.5 nm av. size. The microscopic (AFM, SEM, TEM) analzses unveiled spherical shaped particles with 2-69 nm size of the CuO NPs. These nanoparticles were settled in poly-dispersed and non-agglomerated state. They exhibited potential growth inhibitory effect on NDV virus. Based on the results of present work it can be emphasized that nanoparticles synthesized using plant exts. find a place in future nanomedicine.
- 95Tavakoli, A.; Hashemzadeh, M. S. Inhibition of Herpes Simplex Virus Type 1 by Copper Oxide Nanoparticles. J. Virol. Methods 2020, 275, 113688, DOI: 10.1016/j.jviromet.2019.11368895Inhibition of herpes simplex virus type 1 by copper oxide nanoparticlesTavakoli, Ahmad; Hashemzadeh, Mohammad SadeghJournal of Virological Methods (2020), 275 (), 113688CODEN: JVMEDH; ISSN:0166-0934. (Elsevier B.V.)There are accumulating reports of the emergence of drug-resistant strains of HSV-1 that have become a barrier to successful treatment of HSV-1 infection. Therefore, there is a pressing need to identify and evaluate alternative antiherpetic agents. The aim of the present study was to investigate the effect of copper oxide nanoparticles (CuO-NPs) on HSV-1 infection. The MTT assay was applied to examine the cytotoxic effects of CuO-NPs on Vero cells. Antiherpetic potency was detd. using the TCID50 and quant. Real-Time PCR assays. To evaluate the inhibitory impact of CuO-NPs on the expression of viral antigens, an indirect immunofluorescence assay (IFA) was performed. Acyclovir was used as a ref. drug in all expts. Exposure of HSV-1 with CuO-NPs at the highest non-toxic concn. (100 ug/mL) resulted in 2.8 log10 TCID50 redn. in infectious virus titer as compared with virus control (P < 0.0001). This concn. of CuO-NPs was assocd. with 83.3% inhibition rate, which was estd. based on the HSV-1 viral load compared to virus control. Our findings demonstrated that CuO-NPs are assocd. with a significant antiviral potency against HSV-1. This feature shows strong potential for CuO-NPs to be used in topical formulations for the treatment of orolabial or genital herpetic lesions.
- 96Broglie, J. J.; Alston, B.; Yang, C.; Ma, L.; Adcock, A. F.; Chen, W.; Yang, L. Antiviral Activity of Gold/Copper Sulfide Core/Shell Nanoparticles against Human Norovirus Virus-Like Particles. PLoS One 2015, 10, e0141050, DOI: 10.1371/journal.pone.014105096Antiviral activity of gold/copper sulfide core/shell nanoparticles against human norovirus virus-like particlesBroglie, Jessica Jenkins; Alston, Brittny; Yang, Chang; Ma, Lun; Adcock, Audrey F.; Chen, Wei; Yang, LijuPLoS One (2015), 10 (10), e0141050/1-e0141050/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Human norovirus is a leading cause of acute gastroenteritis worldwide in a plethora of residential and com. settings, including restaurants, schools, and hospitals. Methods for easily detecting the virus and for treating and preventing infection are crit. to stopping norovirus outbreaks, and inactivation via nanoparticles (NPs) is a more universal and attractive alternative to other phys. and chem. approaches. Using norovirus GI.1 (Norwalk) virus-like particles (VLPs) as a model viral system, this study characterized the antiviral activity of Au/CuS core/shell nanoparticles (NPs) against GI.1 VLPs for the rapid inactivation of HuNoV. Inactivation of VLPs (GI.1) by Au/CuS NPs evaluated using an absorbancebased ELISA indicated that treatment with 0.083 μM NPs for 10 min inactivated ∼50% VLPs in a 0.37 μg/mL VLP soln. and 0.83 μM NPs for 10 min completely inactivated the VLPs. Increasing nanoparticle concn. and/or VLP-NP contact time significantly increased the virucidal efficacy of Au/CuS NPs. Changes to the VLP particle morphol., size, and capsid protein were characterized using dynamic light scattering, transmission electron microscopy, and Western blot anal. The strategy reported here provides the first reported proof-of-concept Au/CuS NPs-based virucide for rapidly inactivating human norovirus.
- 97Hang, X.; Peng, H.; Song, H.; Qi, Z.; Miao, X.; Xu, W. Antiviral Activity of Cuprous Oxide Nanoparticles against Hepatitis C Virus in Vitro. J. Virol. Methods 2015, 222, 150– 157, DOI: 10.1016/j.jviromet.2015.06.01097Antiviral activity of cuprous oxide nanoparticles against Hepatitis C Virus in vitroHang, Xiaofeng; Peng, Haoran; Song, Hongyuan; Qi, Zhongtian; Miao, Xiaohui; Xu, WenshengJournal of Virological Methods (2015), 222 (), 150-157CODEN: JVMEDH; ISSN:0166-0934. (Elsevier B.V.)Small mol. inhibitors in combination with or without interferon have improved sustained antiviral responses against Hepatitis C Virus (HCV) infection. Nonetheless, resistance to these inhibitors is expected to emerge rapidly due to the high mutation rate of the virus. Thus, new antiviral drugs, in combination with currently available therapies, are urgently needed to treat HCV infection. In the present study, we evaluated the antiviral efficacy of cuprous oxide nanoparticles (CO-NPs) against HCV in the HCVcc/Huh7.5.1 cell culture system. CO-NPs were able to significantly inhibit the infectivity of HCVcc at a non-cytotoxic concn. In addn., CO-NPs inhibited the entry of HCV pseudoparticle (HCVpp), including genotypes 1a, 1b, and 2a, while no effect on HCV replication was obsd. Further time-of-addn. expt. indicated that CO-NPs blocked HCV infection both at the attachment and entry stages. In conclusion, we report that CO-NPs can act as an anti-HCV agent by targeting the binding of infectious HCV particles to hepatic cells and the virus entry into the cells. These findings suggest that CO-NPs may have novel roles in the treatment of patients with chronic hepatitis C.
- 98Ishida, T. Antiviral Activities of Cu 2+ Ions in Viral Prevention, Replication, RNA Degradation, and for Antiviral Efficacies of Lytic Virus, ROS-Mediated Virus, Copper Chelation. World Sci. News 2018, 99 (May), 148– 16898Antiviral activities of Cu2+ ions in viral prevention, replication, RNA degradation, and for antiviral efficacies of lytic virus, ROS-mediated virus, copper chelationIshida, TsuneoWorld Scientific News (2018), 99 (), 148-168CODEN: WSNOAZ; ISSN:2392-2192. (Scientific Publishing House "DARWIN")Copper has been known for decades that marked changes of micronutrient homeostasis in the host are accompanied by infection or inflammation. Copper levels in the serum are significantly elevated in response to inflammation that copper accumulates at sites of inflammation. Easily oxidized copper oxide nanoparticles (CuONPs) are widely used as catalysts that the ability of CuONPs to reduce bacterial population and virus application is enhanced. The mechanism of copper-mediated inactivation of herpes simplex virus (HSV) is by which cupric ions oxidatively damage biomols. Virus-mediated subjugation and modulation of host lipids during infection that the life cycle of most viruses proceeds through a series of basic steps: binding and internalization, fusion, uncoating, of the viral genome, its replication, assembly of new particles, and budding or release of the newly made viruses. The HIV-1 protein Vpu is an 81-amino-acid (16-kDa) type I which the presence of Vpu leads to the degrdn. of BST-2 via an endosome-lysosome degrdn. pathway. Oxidative degrdn. by a Cu-metalloenzyme, and ubiquitin-mediated degrdn. of cellular proteins were exploited. Copper can disrupt the lytic cycle of the Coccolithovirus. Lysins represent a novel class of anti-infectives derived from bacteriophage which lysins are bacterial cell wall hydrolytic enzymes that selectively and rapidly kill specific bacteria. Regarding copper induced cellular toxicity, several mechanisms have been proposed based on the formations of ROS by free Cu ions as cupric and cuprous ions can participate in redox reactions. ROS (O2-,•OH, OH-), Cu+ and H2O2 play the important roles for viral inactivations. Thujaplicin-copper chelates inhibit influenza virus-induced apoptosis. Pyrrolidine dithiocarbamate as a metal ion binding agent inhibits the activity of the viral proteases of polyprotein processing and RNA replication of HRV. Chelation enables metals are capable of ligand scavenging via complexation, since reverse transcriptase enzyme inhibits the growth and replication of RNA tumor viruses. Thus, copper complex and copper chelation enhance antiviral efficacy.
- 99Borkow, G.; Zhou, S. S.; Page, T.; Gabbay, J. A Novel Anti-Influenza Copper Oxide Containing Respiratory Face Mask. PLoS One 2010, 5 (6), e11295, DOI: 10.1371/journal.pone.0011295There is no corresponding record for this reference.
- 100Sucipto, T. H.; Churrotin, S.; Setyawati, H.; Kotaki, T.; Martak, F.; Soegijanto, S. Antiviral Activity of Copper(II) Chloride Dihydrate against Dengue Virus Type-2 IN Vero Cell Indones. J. Trop. Infect. Dis. 2017, 6 (4), 84, DOI: 10.20473/ijtid.v6i4.3806There is no corresponding record for this reference.
- 101Shionoiri, N.; Sato, T.; Fujimori, Y.; Nakayama, T.; Nemoto, M.; Matsunaga, T.; Tanaka, T. Investigation of the Antiviral Properties of Copper Iodide Nanoparticles against Feline Calicivirus. J. Biosci. Bioeng. 2012, 113 (5), 580– 586, DOI: 10.1016/j.jbiosc.2011.12.006101Investigation of the antiviral properties of copper iodide nanoparticles against feline calicivirusShionoiri, Nozomi; Sato, Tetsuya; Fujimori, Yoshie; Nakayama, Tsuruo; Nemoto, Michiko; Matsunaga, Tadashi; Tanaka, TsuyoshiJournal of Bioscience and Bioengineering (2012), 113 (5), 580-586CODEN: JBBIF6; ISSN:1389-1723. (Society for Biotechnology, Japan)This study demonstrated the antiviral properties of copper iodide (CuI) nanoparticles against the non-enveloped virus feline calicivirus (FCV) as a surrogate for human norovirus. The effect of CuI nanoparticles on FCV infectivity to Crandell-Rees feline kidney (CRFK) cells was elucidated. The infectivity of FCV to CRFK cells was greatly reduced by 7 orders of magnitude at 1000 μg ml-1 CuI nanoparticles. At the conditions, ESR (ESR) anal. proved hydroxyl radical prodn. in CuI nanoparticle suspension. Furthermore, amino acid oxidn. in the viral capsid protein of FCV was detd. by nanoflow liq. chromatog.-mass spectrometric (nano LC-MS) anal. The use of CuI nanoparticles showed extremely high antiviral activity against FCV. The high antiviral property of CuI nanoparticles was attributed to Cu+, followed by ROS generation and subsequent capsid protein oxidn. CuI nanoparticles could be proposed as useful sources of a continuous supply of Cu+ ions for efficient virus inactivation. Furthermore, this study brings new insights into toxic actions of copper iodide nanoparticles against viruses.
- 102Escoffery, C. C.; Dunn, I.; Patel, H.; Yan, S.; Shukla, S. A Novel Approach to Antiviral COVID-19 Masks, 2020; https://soe.rutgers.edu/sites/default/files/imce/pdfs/GSET_2020___COVID_Masks.pdf.There is no corresponding record for this reference.
- 103Shi, M.; De Mesy Bentley, K. L.; Palui, G.; Mattoussi, H.; Elder, A.; Yang, H. The Roles of Surface Chemistry, Dissolution Rate, and Delivered Dose in the Cytotoxicity of Copper Nanoparticles †. Nanoscale 2017, 9, 4739, DOI: 10.1039/C6NR09102D103The roles of surface chemistry, dissolution rate, and delivered dose in the cytotoxicity of copper nanoparticlesShi, Miao; de Mesy Bentley, Karen L.; Palui, Goutam; Mattoussi, Hedi; Elder, Alison; Yang, HongNanoscale (2017), 9 (14), 4739-4750CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)The understanding of nanoparticle (NP) cytotoxicity is challenging because of incomplete information about physicochem. changes particles undergo once they come into contact with biol. fluids. It is therefore essential to characterize changes in NP properties to better understand their biol. fate and effects in mammalian cells. In this paper, we present a study on the effect of particle surface oxidn. and dissoln. rates of Cu NPs. Particle dissoln., cell-assocd. Cu doses, and oxidative stress responses in A549 luciferase reporter cells were examd. for Cu NPs modified with mercaptocarboxylic acids with different carbon chain lengths and a thiotic acid appended-PEG ligand (TA). We found that these Cu NPs released ionic species together with small particles upon oxidn. and that surface chem. influenced the morphol. and dissoln. rate. The dissoln. rate was also shown to impact both the cellular Cu dosimetry and assocd. oxidative stress responses. The convergent results from dissoln. and dosimetry measurements demonstrate that both intracellular and extracellular (i.e., NP uptake-independent) release of ionic species from Cu NPs greatly affect the cytotoxicity.
- 104Zheng, K.; Dai, X.; Lu, M.; Hüser, N.; Taccardi, N.; Boccaccini, A. R. Synthesis of Copper-Containing Bioactive Glass Nanoparticles Using a Modified Stöber Method for Biomedical Applications. Colloids Surf., B 2017, 150, 159– 167, DOI: 10.1016/j.colsurfb.2016.11.016104Synthesis of copper-containing bioactive glass nanoparticles using a modified Stober method for biomedical applicationsZheng, Kai; Dai, Xinyi; Lu, Miao; Hueser, Norbert; Taccardi, Nicola; Boccaccini, Aldo. R.Colloids and Surfaces, B: Biointerfaces (2017), 150 (), 159-167CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)Copper (Cu)-contg. bioactive glasses (BGs) are attracting attention for bone regeneration and wound healing since they have bone-bonding capability and potential osteogenesis and angiogenesis properties. In this study, highly dispersed and spherical Cu-contg. bioactive glass nanoparticles (Cu-BGNs) were successfully synthesized via a modified Stober method. The content of incorporated Cu in the particles could be tailored by adjusting the amt. of the added Cu precursor, a procedure that had no significant effects on the morphol. and structural characteristics of the nanoparticles. Cu-BGNs exhibited satisfactory apatite-forming ability, as a large quantity of apatite could form on Cu-BGNs pellets after immersion in simulated body fluid for just 3 days. The incorporation of Cu exhibited pos. effects on the apatite formation. In addn., both Si and Cu ions were released from the Cu-BGN in a sustained manner for at least 14 days in cell culture medium, indicating the potential of the BGN as promising carriers for delivering therapeutic Cu ions. Moreover, Cu-BGNs showed no significant cytotoxicity towards human mesenchymal stem cells and fibroblast cells at concns. of 100, 10 and 1μg/mL. Taken together, the results suggest that Cu-BGNs are promising nanoparticulate fillers to develop nanocomposites for biomedical applications esp. in bone regeneration and wound healing.
- 105Santi, M.; Mapanao, A. K.; Cassano, D.; Vlamidis, Y.; Cappello, V.; Voliani, V. Endogenously-Activated Ultrasmall-in-Nano Theranostics: Assessment on 3D Head and Neck Squamous Cell Carcinomas. Cancers 2020, 12 (5), 1063, DOI: 10.3390/cancers12051063105Endogenously-activated ultrasmall-in-nanotherapeutics: assessment on 3D Head and NeckSquamous Cell CarcinomasSanti, Melissa; Mapanao, Ana Katrina; Cassano, Domenico; Vlamidis, Ylea; Cappello, Valentina; Voliani, ValerioCancers (2020), 12 (5), 1063CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)Neg. or pos. HPV-assocd. Head and Neck Squamous Cell Carcinomas (HNSCCs) are high recurrence neoplasms usually resulting in a poor prognosis, mainly due to metastasis formation. Despite the low overall patient survival rate and the severe side effects, the treatment of choice is still cisplatin-based chemotherapy. Here, we report a straightforward protocol for the prodn. of high throughput 3D models of neg. or pos. HPV-assocd. HNSCCs, together with their employment in the therapeutic evaluation of gold ultrasmall-in-nano architectures comprising an endogenously-activatable cisplatin prodrug. Beyond enhancing the biosafety of cisplatin, our approach paves the way for the establishment of synergistic co-therapies for HNSCCs based on excretable noble metals.
- 106Cassano, D.; Pocoví-Martínez, S.; Voliani, V. Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to Clinics. Bioconjugate Chem. 2018, 29 (1), 4– 16, DOI: 10.1021/acs.bioconjchem.7b00664106Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to ClinicsCassano, Domenico; Pocovi-Martinez, Salvador; Voliani, ValerioBioconjugate Chemistry (2018), 29 (1), 4-16CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Currently, nanomaterials are of widespread use in daily com. products. However, the most-promising and potentially impacting application is in the medical field. In particular, nanosized noble metals hold the promise of shifting the current medical paradigms for the detection and therapy of neoplasms thanks to the: (i) localized surface plasmon resonances (LSPRs), (ii) high electron d., and (iii) suitability for straightforward development of all-in-one nanoplatforms. Nonetheless, there is still no clin. approved noble metal nanomaterial for cancer therapy and diagnostics. The clin. translation of noble metal nanoparticles (NPs) is mainly prevented by the issue of persistence in organism after the medical action. Such persistence increases the likelihood of toxicity and the interference with common medical diagnoses. Size redn. to ultrasmall nanoparticles (USNPs) is a suitable approach to promoting metal excretion by the renal pathway. However, most of the functionalities of NPs are lost or severely altered in USNPs, jeopardizing clin. applications. A ground-breaking advance to jointly combine the appealing behaviors of NPs with metal excretion relies on the ultrasmall-in-nano approach for the design of all-in-one degradable nanoplatforms composed of USNPs. Such nanoarchitectures might lead to the delivery of a novel paradigm for nanotechnol., enabling the translation of noble metal nanomaterials to clinics to treat carcinomas in a less-invasive and more-efficient manner. This Review covers the recent progresses related to this exciting approach. The most-significant nanoarchitectures designed with the ultrasmall-in-nano approach are discussed, and perspectives on these nanoarchitectures are provided.
- 107Armanetti, P.; Pocoví-Martínez, S.; Flori, A.; Avigo, C.; Cassano, D.; Menichetti, L.; Voliani, V. Dual Photoacoustic/Ultrasound Multi-Parametric Imaging from Passion Fruit-Like Nano-Architectures. Nanomedicine 2018, 14 (6), 1787– 1795, DOI: 10.1016/j.nano.2018.05.007107Dual photoacoustic/ultrasound multi-parametric imaging from passion fruit-like nano-architecturesArmanetti, Paolo; Pocovi-Martinez, Salvador; Flori, Alessandra; Avigo, Cinzia; Cassano, Domenico; Menichetti, Luca; Voliani, ValerioNanomedicine (New York, NY, United States) (2018), 14 (6), 1787-1795CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Ultrasound (US) imaging is a well-established diagnostic technique to image soft tissues in real time, while photoacoustic (PA) is an emerging imaging technique employed to collect mol. information. Integration of PA and US imaging provides complementary information enhancing diagnostic accuracy without employing ionizing radiations. The development of contrast agents able to combine PA and US features is pivotal to improve the significance of PAUS imaging and for PAUS-guided treatment of neoplasms. Here, we demonstrate in relevant ex-vivo models that disassembling passion fruit-like nano-architectures (pfNAs) can be employed in PAUS imaging. pfNAs are composed by silica nanocapsules comprising aggregates of com. NIR-dyes-modified polymers and ultrasmall gold nanoparticles. The intrinsic US and PA features of pfNAs have been fully characterized and validated in tissue-mimicking materials and in ex vivo prepns. Moreover, the application of a multi-parametric approach has allowed the increase of information extrapolated from collected images for a fine texture anal.
- 108Cassano, D.; Mapanao, A.-K.; Summa, M.; Vlamidis, Y.; Giannone, G.; Santi, M.; Guzzolino, E.; Pitto, L.; Poliseno, L.; Bertorelli, R.; Voliani, V. Biosafety and Biokinetics of Noble Metals: The Impact of Their Chemical Nature. ACS Appl. Bio Mater. 2019, 2 (10), 4464– 4470, DOI: 10.1021/acsabm.9b00630108Biosafety and Biokinetics of Noble Metals: The Impact of Their Chemical NatureCassano, Domenico; Mapanao, Ana-Katrina; Summa, Maria; Vlamidis, Ylea; Giannone, Giulia; Santi, Melissa; Guzzolino, Elena; Pitto, Letizia; Poliseno, Laura; Bertorelli, Rosalia; Voliani, ValerioACS Applied Bio Materials (2019), 2 (10), 4464-4470CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)Effective excretion of nanostructured noble metals is still one of the most challenging bottlenecks for their employment in clin. practice. Besides the persistence issue, the clin. translation of inorg. nanomaterials is also affected by a bewildering lack of investigations regarding their quant. biokinetics. Here, we have quant. correlated the chem. nature of the three most interesting noble metals for biomedical applications to their biosafety and biokinetics in, resp., zebrafish and murine models. Gold, silver, and platinum ultrasmall-in-nano architectures with comparable size elicit, after i.v. administration, different excretion pathways depending on their intrinsic metallic nature. Understanding the in vivo fate of noble metal nanoparticles is a significant breakthrough to unlock their clin. employment for the establishment of treatments for neoplasms, infectious diseases, and neurol. disorders.
- 109Mapanao, A. K.; Giannone, G.; Summa, M.; Ermini, M. L.; Zamborlin, A.; Santi, M.; Cassano, D.; Bertorelli, R.; Voliani, V. Biokinetics and clearance of inhaled gold ultrasmall-in-nano architectures. Nanoscale Adv. 2020, 2, 3815– 3820, DOI: 10.1039/D0NA00521E10900Biokinetics and clearance of inhaled gold ultrasmall-in-nano architecturesMapanao, Ana Katrina; Giannone, Giulia; Summa, Maria; Ermini, Maria Laura; Zamborlin, Agata; Santi, Melissa; Cassano, Domenico; Bertorelli, Rosalia; Voliani, ValerioNanoscale Advances (2020), 2 (9), 3815-3820CODEN: NAADAI; ISSN:2516-0230. (Royal Society of Chemistry)Among an organism's entry portals, the respiratory tract is one of the most promising routes for non-invasive administration of therapeutics for local and systemic delivery. On the other hand, it is the subtlest to protect from environmental pollution and microbial occurrences. Here, the biokinetics, distribution, and clearance trends of gold ultrasmall-in-nano architectures administered through a single intranasal application have been quant. evaluated. Apart from reaching the lung parenchyma, the (bio)degradable nano-architectures are able to translocate as well to secondary organs and be almost completely excreted within 10 days. These findings further support the clin. relevance of plasmonic nanomaterials for oncol. and infectious disease treatment and management. Notably, this investigation also provides crucial information regarding the assocd. risks as a consequence of the pulmonary delivery of nanoparticles.
- 110d’Amora, M.; Cassano, D.; Pocovi-Martinez, S.; Giordani, S.; Voliani, V. Biodistribution and biocompatibility of passion fruit-like nano-architectures in zebrafish. Nanotoxicology 2018, 12, 914– 922, DOI: 10.1080/17435390.2018.149855110901Biodistribution and biocompatibility of passion fruit-like nano-architectures in zebrafishd'Amora, Marta; Cassano, Domenico; Pocovi-Martinez, Salvador; Giordani, Silvia; Voliani, ValerioNanotoxicology (2018), 12 (8), 914-922CODEN: NANOGK; ISSN:1743-5404. (Taylor & Francis Ltd.)Passion fruit-like nano-architectures (NAs) are all-in-one platforms of increasing interest for the translation of metal nanoparticles into clinics. NAs are nature-inspired disassembling inorg. theranostics, which jointly combine most of the appealing behaviors of noble metal nanoparticles with their potential organism excretion. Despite their unique and promising properties, NAs in vivo interactions and potential adverse effects have not yet been investigated. In this study, we employ zebrafish (Danio Rerio) to assess the development toxicity of NAs as well as their uptake and bioaccumulation at different stages of growth. The evaluation of multiple endpoints related to the toxicity clearly indicates that NAs do not induce mortality, developmental defects, or alterations on the hatching rate and behavior of zebrafish. Moreover, the anal. of nanostructures uptake and biodistribution demonstrates that NAs are successfully internalized and present a specific localization. Overall, our results demonstrate that NAs are able to pass through the embryos chorion and accumulate in specific tissues, exhibiting an impressive biocompatibility.
- 111Yin, S. N.; Liu, Y.; Zhou, C.; Yang, S. Glutathione-Mediated Cu(I)/Cu(II) Complexes: Valence-Dependent Effects on Clearance and in Vivo Imaging Application. Nanomaterials 2017, 7 (6), 132, DOI: 10.3390/nano7060132109Glutathione-mediated Cu(I)/Cu(II) complexes: valence-dependent effects on clearance and in vivo imaging applicationYin, Su-Na; Liu, Yuanyuan; Zhou, Chen; Yang, ShengyangNanomaterials (2017), 7 (6), 132/1-132/10CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)Contrast imaging agents need to be cleared in a reasonable time (less than 72 h), so it is quite urgent to understand the structure, biocompatibility, and metab. features of imaging agents. In this work, luminescent Cu(I)-GSH complex and their deriv. oxidized Cu(II)-GSSG complex have been easily synthesized. Through systematically probing the renal clearance and biodistribution of the as-prepd. copper complexes, we found that Cu(I)-GSH complex revealed much more efficient renal clearance and remarkably lower liver accumulation than that of their oxidn. states, which could be due to strong protein binding of partial forms of Cu(II)-GSSG complex. Besides, we also attempted to incorporate radioactive copper-64 into Cu(I)-GSH complex for the synthesis of radioactive contrast agent. Indeed, the as-prepd. radioactive Cu(I)-GSH complex also showed consistent high efficiency renal excretion, allowing them to be potential PET imaging agents in clin. translation.
- 112Yang, S.; Sun, S.; Zhou, C.; Hao, G.; Liu, J.; Ramezani, S.; Yu, M.; Sun, X.; Zheng, J. Renal Clearance and Degradation of Glutathione-Coated Copper Nanoparticles. Bioconjugate Chem. 2015, 26 (3), 511– 519, DOI: 10.1021/acs.bioconjchem.5b00003110Renal Clearance and Degradation of Glutathione-Coated Copper NanoparticlesYang, Shengyang; Sun, Shasha; Zhou, Chen; Hao, Guiyang; Liu, Jinbin; Ramezani, Saleh; Yu, Mengxiao; Sun, Xiankai; Zheng, JieBioconjugate Chemistry (2015), 26 (3), 511-519CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Degrdn. of inorg. nanoparticles (NPs) into small mol. complexes is often obsd. in the physiol. environment; however, how this process influences renal clearance of inorg. NPs is largely unknown. By systematically comparing renal clearance of degradable luminescent glutathione coated copper NPs (GS-CuNPs) and their dissocd. products, Cu(II)-glutathione disulfide (GSSG) complexes (Cu(II)-GSSG), the authors found that GS-CuNPs were eliminated through the urinary system surprisingly faster and accumulated in the liver much less than their smaller dissocn. counterparts. With assistance of radiochem. and positron emission tomog. (PET) imaging, the authors found that the obsd. "nano size" effect in enhancing renal clearance is attributed to the fact that GS-CuNPs are more resistant to serum protein adsorption than Cu(II)-GSSG. In addn., since dissocn. of GS-CuNPs follows zero-order chem. kinetics, their renal clearance and biodistribution also depend on initial injection doses and their dissocn. processes. Quant. understanding of size effect and other factors involved in renal clearance and biodistribution of degradable inorg. NPs will lay down a foundation for further development of renal-clearable inorg. NPs with minimized nanotoxicity.
- 113Liang, G.; Jin, X.; Qin, H.; Xing, D. Glutathione-Capped, Renal-Clearable CuS Nanodots for Photoacoustic Imaging and Photothermal Therapy. J. Mater. Chem. B 2017, 5 (31), 6366– 6375, DOI: 10.1039/C7TB01517H111Glutathione-capped, renal-clearable CuS nanodots for photoacoustic imaging and photothermal therapyLiang, Guohai; Jin, Xudong; Qin, Huan; Xing, DaJournal of Materials Chemistry B: Materials for Biology and Medicine (2017), 5 (31), 6366-6375CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)The development of functional nanomaterials that undergo renal clearance is of fundamental importance to their in vivo biomedical applications. The authors report a one-pot method for the prepn. of ultrasmall copper sulfide nanodots capped with a small natural tripeptide glutathione (GSH-CuS NDs). The GSH-CuS NDs had a hydrodynamic diam. of 5.8 nm, smaller than the reported polymer-coated CuS NDs with similar core sizes, and exhibited strong optical absorption and conversion at the near-IR (NIR) region, leading to a sufficient photohyperthermic effect under the irradn. of a 980. nm laser. In vivo studies showed that the GSH-CuS NDs could induce significant photoacoustic imaging signal enhancement and remarkable photothermal therapy efficacy. Importantly, biodistribution studies and MRI imaging showed that the GSH-CuS NDs could freely circulate in the blood pool without undesirable accumulation in the liver and spleen, and could be naturally removed from the body through renal clearance, making them attractive for practical theranostic applications.
- 114Du, B.; Yu, M.; Zheng, J. Transport and Interactions of Nanoparticles in the Kidneys. Nat. Rev. Mater. 2018, 3, 358– 374, DOI: 10.1038/s41578-018-0038-3There is no corresponding record for this reference.
- 115Du, B.; Jiang, X.; Das, A.; Zhou, Q.; Yu, M.; Jin, R.; Zheng, J. Glomerular Barrier Behaves as an Atomically Precise Bandpass Filter in a Sub-Nanometre Regime. Nat. Nanotechnol. 2017, 12 (11), 1096– 1102, DOI: 10.1038/nnano.2017.170113Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regimeDu, Bujie; Jiang, Xingya; Das, Anindita; Zhou, Qinhan; Yu, Mengxiao; Jin, Rongchao; Zheng, JieNature Nanotechnology (2017), 12 (11), 1096-1102CODEN: NNAABX; ISSN:1748-3387. (Nature Research)The glomerular filtration barrier is known as a 'size cutoff' slit, which retains nanoparticles or proteins larger than 6-8 nm in the body and rapidly excretes smaller ones through the kidneys. However, in the sub-nanometer size regime, we have found that this barrier behaves as an atomically precise 'bandpass' filter to significantly slow down renal clearance of few-atom gold nanoclusters (AuNCs) with the same surface ligands but different sizes (Au18, Au15 and Au10-11). Compared to Au25 (∼1.0 nm), just few-atom decreases in size result in four- to ninefold redns. in renal clearance efficiency in the early elimination stage, because the smaller AuNCs are more readily trapped by the glomerular glycocalyx than larger ones. This unique in vivo nano-bio interaction in the sub-nanometer regime also slows down the extravasation of sub-nanometer AuNCs from normal blood vessels and enhances their passive targeting to cancerous tissues through an enhanced permeability and retention effect. This discovery highlights the size precision in the body's response to nanoparticles and opens a new pathway to develop nanomedicines for many diseases assocd. with glycocalyx dysfunction.
- 116Han, Y.; Wang, T.; Liu, H.; Zhang, S.; Zhang, H.; Li, M.; Sun, Q.; Li, Z. The Release and Detection of Copper Ions from Ultrasmall Theranostic Cu2-XSe Nanoparticles. Nanoscale 2019, 11 (24), 11819– 11829, DOI: 10.1039/C9NR02884F114The release and detection of copper ions from ultrasmall theranostic Cu2-xSe nanoparticlesHan, Yaobao; Wang, Tingting; Liu, Hanghang; Zhang, Shaohua; Zhang, Hao; Li, Mengting; Sun, Qiao; Li, ZhenNanoscale (2019), 11 (24), 11819-11829CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)Nanoscale copper chalcogenides have been widely used in nanomedicine, however, their pharmacokinetics, degrdn., and biol. effects of released copper ions are usually overlooked, which are crucial for their future clin. translation. Herein, we report the in vitro and in vivo release of copper ions from polyvinylpyrrolidone (PVP) functionalized ultrasmall copper selenide (Cu2-xSe) theranostic nanoparticles. We synthesized a Cu2+-specific fluorescent probe (NCM), which can quickly and specifically react with copper ions to exhibit very strong near IR fluorescence. The in vitro study shows that copper ions can be slowly released from Cu2-xSe nanoparticles in aq. soln. with the progress of their oxidn. The release of copper ions from Cu2-xSe nanoparticles in RAW 264.7 murine macrophages is very fast, evidenced by the gradual increase of fluorescence intensity and the diffusion of fluorescence from cytoplasm into nuclei. We also demonstrate the distribution, degrdn., and the metab. of ultrasmall Cu2-xSe nanoparticles by the in vivo fluorescence imaging, the blood routine test, blood biochem. and histol. anal., and the characterization of copper transport and binding proteins. The results show that ultrasmall Cu2-xSe nanoparticles were mainly eliminated through feces and urine from the body within 72 h after i.v. injection, and the released copper ions did not cause severe toxicity. Our research highlights the great potential of copper chalcogenide nanoparticles in nanomedicine.
- 117Feng, W.; Nie, W.; Cheng, Y.; Zhou, X.; Chen, L.; Qiu, K.; Chen, Z.; Zhu, M.; He, C. In Vitro and in Vivo Toxicity Studies of Copper Sulfide Nanoplates for Potential Photothermal Applications. Nanomedicine 2015, 11 (4), 901– 912, DOI: 10.1016/j.nano.2014.12.015115In vitro and in vivo toxicity studies of copper sulfide nanoplates for potential photothermal applicationsFeng, Wei; Nie, Wei; Cheng, Yanhua; Zhou, Xiaojun; Chen, Liang; Qiu, Kexin; Chen, Zhigang; Zhu, Meifang; He, ChuanglongNanomedicine (New York, NY, United States) (2015), 11 (4), 901-912CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Copper sulfide (CuS) has emerged as a promising photothermal agent. However, its potential toxic effects still remained poorly understood. Herein, CuS nanoplates were synthesized for toxicity assessment. The in vitro study indicated that the cell viability decreased when CuS nanoplate concn. was higher than 100 μg/mL. CuS nanoplates caused apparent toxicity to HUVEC and RAW 264.7 cells. For acute toxicity, max. tolerated dose and LD 50 were 8.66 and 54.5 mg/kg, resp. Furthermore, the sub-chronic toxicity test results indicated that there was no obvious effect at tested doses during the test period. The biodistribution study showed that i.v. administrated CuS nanoplates were mainly present in the spleen, liver and lung. Taken together, our results shed light on the rational design of CuS nanomaterials to minimize toxicity, thus providing a useful guideline in selecting CuS as the photothermal agent for cancer therapy.
- 118Dey, A.; Manna, S.; Adhikary, J.; Chattopadhyay, S.; De, S.; Chattopadhyay, D.; Roy, S. Biodistribution and Toxickinetic Variances of Chemical and Green Copper Oxide Nanoparticles in Vitro and in Vivo. J. Trace Elem. Med. Biol. 2019, 55, 154– 169, DOI: 10.1016/j.jtemb.2019.06.012116Biodistribution and toxickinetic variances of chemical and green Copper oxide nanoparticles in vitro and in vivoDey, Aditi; Manna, Subhankar; Adhikary, Jaydeep; Chattopadhyay, Sourav; De, Sriparna; Chattopadhyay, Dipankar; Roy, SomenathJournal of Trace Elements in Medicine and Biology (2019), 55 (), 154-169CODEN: JTEBFO; ISSN:0946-672X. (Elsevier GmbH)In this study, chem. (S1) and green (S2) Copper Oxide nanoparticles (NPs) were synthesized to det. their biodistribution and toxicokinetic variances in vitro and in vivo. Both NPs significantly released Copper ions (Cu) in lymphocytes and were primarily deposited in the mononuclear phagocyte system (MPS) such as the liver and spleen in mice. In particular, S2NPs seemed to be prominently stored in the spleen, whereas the S1NPs were widely stored in more organs including the liver, heart, lungs, kidney and intestine. The circulation in the blood and fecal excretions both showed higher S2NPs contents resp. Measurements of cell viability, Hemolysis assay, Reactive Oxygen Species (ROS) generation, biochem. estn. and apoptotic or necrotic study in lymphocytes after 24 h and measurements of body and organ wt., serum chem. evaluation, cytokines level, protein expressions and histopathol. of Balb/C mice after 15 days indicated significant toxicity difference between the S1NPs and S2NPs. Our observations proved that the NPs physiochem. properties influence toxicity and Biodistribution profiles in vitro and in vivo.
- 119Cholewińska, E.; Ognik, K.; Fotschki, B.; Zduńczyk, Z.; Juśkiewicz, J. Comparison of the Effect of Dietary Copper Nanoparticles and One Copper(II) Salt on the Copper Biodistribution and Gastrointestinal and Hepatic Morphology and Function in a Rat Model. PLoS One 2018, 13 (5), e0197083, DOI: 10.1371/journal.pone.0197083117Comparison of the effect of dietary copper nanoparticles and one copper (II) salt on the copper biodistribution and gastrointestinal and hepatic morphology and function in a rat modelCholewinska, Ewelina; Ognik, Katarzyna; Fotschki, Bartosz; Zdunczyk, Zenon; Juskiewicz, JerzyPLoS One (2018), 13 (5), e0197083/1-e0197083/23CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The aim of the study was to investigate the effect of two forms (CuCO3 (CuS); and Cu nanoparticles (CuNP)) and dosages (std. 6.5 mg/kg (H), half of the std. (L)) of addnl. dietary Cu administered to growing rats on gastrointestinal and hepatic function and morphol. Copper in the form of CuNP vs CuS caused lower Cu faecal/urinal excretion and increased Cu accumulation in the brain tissue. Hepatic high-grade hydropic degeneration and necrotic lesions were obsd. only in the CuNP-H animals. In the lower gut, the dietary application of CuNP stifled bacterial enzymic activity of caecal gut microbiota and resulted in lower SCFA prodn. That diminishing effect of CuNP on caecal microbiota activity was accompanied by a relative increase in the secretion of glycoside hydrolases by bacterial cells. The results showed that in comparison to Cu from CuCO3, Cu nanoparticles to a greater extent were absorbed from the intestine, accumulated in brain tissue, exerted antimicrobial effect in the caecum, and at higher dietary dose caused damages in the liver of rats.
- 120Lei, R.; Yang, B.; Wu, C.; Liao, M.; Ding, R.; Wang, Q. Mitochondrial Dysfunction and Oxidative Damage in the Liver and Kidney of Rats Following Exposure to Copper Nanoparticles for Five Consecutive Days. Toxicol. Res. (Cambridge, U. K.) 2015, 4 (2), 351– 364, DOI: 10.1039/C4TX00156G118Mitochondrial dysfunction and oxidative damage in the liver and kidney of rats following exposure to copper nanoparticles for five consecutive daysLei, Ronghui; Yang, Baohua; Wu, Chunqi; Liao, Mingyang; Ding, Rigao; Wang, QuanjunToxicology Research (Cambridge, United Kingdom) (2015), 4 (2), 351-364CODEN: TROEE8; ISSN:2045-4538. (Royal Society of Chemistry)Objective: The goal of the current study was to investigate the mol. mechanisms of copper nanoparticle (CuNP)-induced hepato- and nephrotoxicity by a proteomic anal. that was phenotypically anchored to conventional toxicol. outcomes. Methods: We employed specialized proteomic techniques, namely two-dimensional difference gel electrophoresis coupled with mass spectrometry to analyze the changes in protein expression in rat liver and kidney after 5 days of oral copper nanoparticle administration. Serum biochem. analyses and histopathol. examns. of livers and kidneys of all rats were also performed. Results: All of the results indicated that the adverse effects obsd. in the rats treated with 100 mg kg-1 d-1 nanocopper were less than those induced by 200 mg kg-1 d-1 CuNPs. Exposure to CuNPs at a dose of 200 mg kg-1 d-1 for 5 d can induce overt hepatotoxicity and nephrotoxicity through a mechanism that mainly involves scattered dot hepatocytic necrosis and widespread renal proximal tubule necrosis. In addn., significantly elevated copper accumulation, decreased thiol groups and elevated malondialdehyde levels were also obsd. in the liver and kidney tissues. The perturbed proteins identified in the rat livers and kidneys are mainly involved in the respiratory and energy metabs., antioxidant defense, phase II metab., lipid metab., urea cycle, creatine biosynthesis, intracellular calcium homeostasis, and cytoskeletal organization. No abnormalities were identified in the liver and kidney tissues from the rats treated with 200 mg kg-1 microcopper. Conclusions: The results of this study suggest that mitochondrial dysfunction and oxidative damage may be the initial events in the hepato- and nephrotoxicity of copper nanoparticles. The down-regulation of phase II metabolic enzymes in the liver and the decrease in calcium-binding proteins in the kidney appear to be specific modes of action in these target organs. Our findings offer new directions for future research aiming to identify the specific biomarkers of the hepatotoxicity and nephrotoxicity of copper nanoparticles.
- 121Fahmy, H. M.; Ali, O. A.; Hassan, A. A.; Mohamed, M. A. Biodistribution and Toxicity Assessment of Copper Nanoparticles in the Rat Brain. J. Trace Elem. Med. Biol. 2020, 61, 126505, DOI: 10.1016/j.jtemb.2020.126505119Biodistribution and toxicity assessment of copper nanoparticles in the rat brainFahmy, Heba M.; Ali, Omnia A.; Hassan, Asmaa A.; Mohamed, Maha A.Journal of Trace Elements in Medicine and Biology (2020), 61 (), 126505CODEN: JTEBFO; ISSN:0946-672X. (Elsevier GmbH)The increase in the usage of copper nanoparticles (Cu NPs) in the industrial and medical fields has raised concerns about their possible adverse effects. The present study aims to investigate the potential adverse effects of Cu NPs on the brain of adult male Wistar rats through the estn. of some oxidative stress parameters and acetylcholinesterase (AChE) activity. Cu NPs were prepd. and characterized using different techniques: Dynamic Light Scattering, X-Ray Diffraction, Transmission and SEM, Fourier transform IR Spectroscopy, in addn. to Energy Dispersive X-ray Spectroscopy. Rats were divided into two groups: Cu NPs-treated group (IV injected with 15 mg/kg_13 nm Cu NPs for 2 successive days) and a control group (injected with saline). Rats of the 2 groups were decapitated simultaneously after 48 h of the last injection. The Cu content in different brain areas was analyzed using inductively coupled plasma mass spectrometry. Moreover, the effect of Cu NPs on brain edema was evaluated. The behavior of rats in an open-field was also examd. 24 h post the last injection. Significant increases of Cu content in the cortex, cerebellum, striatum, thalamus and hippocampus were found. Moreover, Cu NPs lead to the induction of oxidative stress condition in the thalamus, hypothamaus and medulla. In addn., Cu NPs induced significant increases in AChE activity in the medulla, hippocampus, striatum besides midbrain. Cu NPs-injected rats showed also decreased exploratory behavior. The results obtained in the present study point to the importance of toxicity assessments in evaluating the efficiency of Cu NPs for the safe implementation in different applications.
- 122Liu, Y.; Gao, Y.; Liu, Y.; Li, B.; Chen, C.; Wu, G. Oxidative Stress and Acute Changes in Murine Brain Tissues after Nasal Instillation of Copper Particles with Different Sizes. J. Nanosci. Nanotechnol. 2014, 14 (6), 4534– 4540, DOI: 10.1166/jnn.2014.8290120Oxidative stress and acute changes in murine brain tissues after nasal instillation of copper particles with different sizesLiu, Yang; Gao, Yuxi; Liu, Ying; Li, Bai; Chen, Chunying; Wu, GangJournal of Nanoscience and Nanotechnology (2014), 14 (6), 4534-4540CODEN: JNNOAR; ISSN:1533-4880. (American Scientific Publishers)We aim to investigate the biol. effects of copper particles on the murine brain and their underlying mechanism after nasal instillation of copper particles. We choose different sizes and different concns. of copper nanoparticles for mice intranasal use. Within one week, the mice were sacrificed. Pathol. lesions of glial cells were detected by immunohistochem. assay. Immunohistochem. assay reveals that glial fibrillary acidic protein (GFAP) increased significantly in all exptl. groups, esp. in nanocopper groups. The ultrastructure of nerve cells was obsd. through TEM, whose results show that there were chromatin congregation and mitochondria shrinkage in the olfactory cells, and that there was increase of endoplasmic reticulum and disassocn. of endoplasmic reticulum ribosomes in hippocampus, particularly in the nanocopper-groups. Oxidative stress indexes were detd. with colorimetric methods. There was no significant increase in the antioxidative enzymes (GPX, GST, SOD) in brain tissues; however, significant increase of malondiadehyde (MDA) contents was only found in the Cu nanoparticle-exposed mice at the high dose of 40 mg per kg body wt. Based on the investigation into the biol. effects of copper nanoparticles (23.5 nm) after intranasal instillation to the mice, we have found that copper particles can indeed enter into the olfactory bulb and then the deeper brain. The inhalation of high dose copper nanoparticles can induce severer lesions of brain in the exptl. mice. The underlying mechanism of copper nanoparticles causing severe brain damage bears little connection with oxidative stress.
- 123Zhang, L.; Ru, B.; Liu, Y.; Li, M.; Li, B.; Wang, L.; Xu, L.; Le Guyader, L.; Chen, C. The Dose-Dependent Toxicological Effects and Potential Perturbation on the Neurotransmitter Secretion in Brain Following Intranasal Instillation of Copper Nanoparticles. Nanotoxicology 2012, 6 (5), 562– 575, DOI: 10.3109/17435390.2011.590906121The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticlesZhang, Lili; Bai, Ru; Liu, Ying; Meng, Li; Li, Bai; Wang, Liming; Xu, Ligeng; Le Guyader, Laurent; Chen, ChunyingNanotoxicology (2012), 6 (5), 562-575CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)Increasing prodn. and application of metallic nanomaterials are likely to result in the release of these particles into the environment. These released nanoparticles may enter into the lungs and the central nervous system (CNS) directly through inhalation, which therefore poses a potential risk to human health. Herein, we focus on the systemic toxicity and potential influence on the neurotransmitter secretion of intranasally instilled copper nanoparticles (23.5 nm) at three different doses. Copper nanoparticle-exposed mice exhibit pathol. lesions at different degrees in certain tissues and esp. in lung tissue as revealed by histopathol. and transmission electron microscopy (TEM) observations. Inductively-coupled plasma mass spectrometry (ICP-MS) results show that the liver, lung and olfactory bulb are the main tissues in which the copper concns. increased significantly after exposure to a higher level of Cu nanoparticles (40 mg/kg of body wt.). The secretion levels of various neurotransmitters changed as well in some brain regions, esp. in the olfactory bulb. Our results indicate that the intranasally instilled copper nanoparticles not only cause the lesions where the copper accumulates, but also affect the neurotransmitter levels in the brain.
- 124Liu, Y.; Gao, Y.; Zhang, L.; Wang, T.; Wang, J.; Jiao, F.; Li, W.; Liu, Y.; Li, Y.; Li, B.; Chai, Z.; Wu, G.; Chen, C. Potential Health Impact on Mice after Nasal Instillation of Nano-Sized Copper Particles and Their Translocation in Mice. J. Nanosci. Nanotechnol. 2009, 9 (11), 6335– 6343, DOI: 10.1166/jnn.2009.1320122Potential health impact on mice after nasal instillation of nano-sized copper particles and their translocation in miceLiu, Yang; Gao, Yuxi; Zhang, Lili; Wang, Tiancheng; Wang, Jiangxue; Jiao, Fang; Li, Wei; Liu, Ying; Li, Yufeng; Li, Bai; Chai, Zhifang; Wu, Gang; Chen, ChunyingJournal of Nanoscience and Nanotechnology (2009), 9 (11), 6335-6343CODEN: JNNOAR; ISSN:1533-4880. (American Scientific Publishers)The purpose of this study is to evaluate the overall toxicity of nasal instilled nanoscale copper particles (23.5 nm) in mice. Pathol. examn., target organs identification, and blood biochem. assay of exptl. mice were carried out in comparison with micro-sized copper particles (17 μm). However, only in the high-dose group of copper nanoparticles (40 mg/kg body wt. instilled for three times in one week), the body wt. of mice were retarded and significant pathol. changes were obsd. There were hydropic degeneration around the central vein and the spotty necrosis of hepatocytes in the liver and swelling in the renal glomerulus, while, severe lesion assocd. with the decreased no. of olfactory cells and the dilapidated laminated structure were also obsd. in the olfactory bulb. The serum biochem. assay also indicated the sign of renal and hepatic lesion. However, there were no obvious pathol. and physiol. damages in the mice after instilling different-sized copper nanoparticles with low dose of 1 mg/kg body wt. The retention and distribution of copper in various tissues show that the liver, kidneys and olfactory bulb are the main accumulated tissues for copper particles, which were detd. by high sensitive element-specific technique of ICP-MS. The copper contents of the liver, kidneys and the olfactory bulb increase significantly at the group of 40 mg/kg compared to the control group, which is in agreement with the histol. changes. Therefore, the data indicate that nasal inhaled copper particles at very high dosage can translocate to other organs and tissues and further induce certain lesions. The present results are helpful to get better understanding of the risk assessment and evaluation for copper nanoparticles.
- 125Pal, A.; Badyal, R. K.; Vasishta, R. K.; Attri, S. V.; Thapa, B. R.; Prasad, R. Biochemical, Histological, and Memory Impairment Effects of Chronic Copper Toxicity: A Model for Non-Wilsonian Brain Copper Toxicosis in Wistar Rat. Biol. Trace Elem. Res. 2013, 153 (1–3), 257– 268, DOI: 10.1007/s12011-013-9665-0123Biochemical, Histological, and Memory Impairment Effects of Chronic Copper Toxicity: A Model for Non-Wilsonian Brain Copper Toxicosis in Wistar RatPal, Amit; Badyal, Rama Kumari; Vasishta, Rakesh Kumar; Attri, Savita Verma; Thapa, Babu Ram; Prasad, RajendraBiological Trace Element Research (2013), 153 (1-3), 257-268CODEN: BTERDG; ISSN:0163-4984. (Springer)Animal models of copper toxicosis rarely exhibit neurol. impairments and increased brain copper accumulation impeding the development of novel therapeutic approaches to treat neurodegenerative diseases having high brain Cu content. The aim of this study was to investigate the effects of i.p. injected copper lactate (0.15 mg Cu/100 g body wt.) daily for 90 days on copper and zinc levels in the liver and hippocampus, on biochem. parameters, and on neurobehavioral functions (by Morris water maze) of male Wistar rats. Copper-administered animals exhibited significantly decreased serum acetylcholinesterase (AChE) activity and impaired neuromuscular coordination and spatial memory compared to control rats. Copper-intoxicated rats showed significant increase in liver and hippocampus copper content (99.1 and 73 % increase, resp.), 40.7 % redn. in hepatic zinc content, and interestingly, 77.1 % increase in hippocampus zinc content with concomitant increase in copper and zinc levels in serum and urine compared to control rats. Massive grade 4 copper depositions and grade 1 copper-assocd. protein in hepatocytes of copper-intoxicated rats were substantiated by rhodanine and orcein stains, resp. Copper-intoxicated rats demonstrated swelling and increase in the no. of astrocytes and copper deposition in the choroid plexus, with degenerated neurons showing pyknotic nuclei and dense eosinophilic cytoplasm. In conclusion, the present study shows the first evidence in vivo that chronic copper toxicity causes impaired spatial memory and neuromuscular coordination, swelling of astrocytes, decreased serum AChE activity, copper deposition in the choroid plexus, neuronal degeneration, and augmented levels of copper and zinc in the hippocampus of male Wistar rats.
- 126Kardos, J.; Héja, L.; Simon, Á.; Jablonkai, I.; Kovács, R.; Jemnitz, K. Copper Signalling: Causes and Consequences 06 Biological Sciences 0601 Biochemistry and Cell Biology. Cell Commun. Signaling 2018, 16, 71, DOI: 10.1186/s12964-018-0277-3124Copper signalling: causes and consequencesKardos, Julianna; Heja, Laszlo; Simon, Agnes; Jablonkai, Istvan; Kovacs, Richard; Jemnitz, KatalinCell Communication and Signaling (2018), 16 (), 71CODEN: CCSEC6; ISSN:1478-811X. (BioMed Central Ltd.)Copper-contg. enzymes perform fundamental functions by activating dioxygen (O2) and therefore allowing chem. energy-transfer for aerobic metab. The copper-dependence of O2 transport, metab. and prodn. of signalling mols. are supported by mol. systems that regulate and preserve tightly-bound static and weakly-bound dynamic cellular copper pools. Disruption of the reducing intracellular environment, characterized by glutathione shortage and ambient Cu(II) abundance drives oxidative stress and interferes with the bidirectional, copper-dependent communication between neurons and astrocytes, eventually leading to various brain disease forms. A deeper understanding of of the regulatory effects of copper on neuro-glia coupling via polyamine metab. may reveal novel copper signalling functions and new directions for therapeutic intervention in brain disorders assocd. with aberrant copper metab.
- 127Shi, Y.; Pilozzi, A. R.; Huang, X. Exposure of CuO Nanoparticles Contributes to Cellular Apoptosis, Redox Stress, and Alzheimer’s Aβ Amyloidosis. Int. J. Environ. Res. Public Health 2020, 17 (3), 1005, DOI: 10.3390/ijerph17031005There is no corresponding record for this reference.
- 128Zhang, H.; Hao, C.; Qu, A.; Sun, M.; Xu, L.; Xu, C.; Kuang, H. Light-Induced Chiral Iron Copper Selenide Nanoparticles Prevent β-Amyloidopathy in Vivo. Angew. Chem., Int. Ed. 2020, 59 (18), 7131– 7138, DOI: 10.1002/anie.202002028126Light-Induced Chiral Iron Copper Selenide Nanoparticles Prevent β-Amyloidopathy In VivoZhang, Hongyu; Hao, Changlong; Qu, Aihua; Sun, Maozhong; Xu, Liguang; Xu, Chuanlai; Kuang, HuaAngewandte Chemie, International Edition (2020), 59 (18), 7131-7138CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The accumulation and deposition of β-amyloid (Aβ) plaques in the brain is considered a potential pathogenic mechanism underlying Alzheimer's disease (AD). Chiral L/D-FexCuySe nanoparticles (NPs) were fabricated that interfere with the self-assembly of Aβ42 monomers and trigger the Aβ42 fibrils in dense structures to become looser monomers under 808 nm near-IR (NIR) illumination. D-FexCuySe NPs have a much higher affinity for Aβ42 fibrils than L-FexCuySe NPs and chiral Cu2-xSe NPs. The chiral FexCuySe NPs also generate more reactive oxygen species (ROS) than chiral Cu2-xSe NPs under NIR-light irradn. In living MN9D cells, D-NPs attenuate the adhesion of Aβ42 to membranes and neuron loss after NIR treatment within 10 min without the photothermal effect. In-vivo expts. showed that D-FexCuySe NPs provide an efficient protection against neuronal damage induced by the deposition of Aβ42 and alleviate symptoms in a mouse model of AD, leading to the recovery of cognitive competence.
- 129Ahamed, M.; Akhtar, M. J.; Alhadlaq, H. A.; Alrokayan, S. A. Assessment of the Lung Toxicity of Copper Oxide Nanoparticles: Current Status. Nanomedicine 2015, 10 (15), 2365– 2377, DOI: 10.2217/nnm.15.72127Assessment of the lung toxicity of copper oxide nanoparticles: current statusAhamed, Maqusood; Akhtar, Mohd Javed; Alhadlaq, Hisham A.; Alrokayan, Salman A.Nanomedicine (London, United Kingdom) (2015), 10 (15), 2365-2377CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Copper oxide nanoparticles (CuO NPs) are being used in several industrial and com. products. Inhalation is one of the most significant routes of metal oxide NP exposure. Hence, the toxicity of CuO NPs in lung tissues is of great concern. In vitro studies have indicated that CuO NPs induce cytotoxicity, oxidative stress and genetic toxicity in cultivated human lung cells. Leaching of Cu ions, reactive oxygen species generation and autophagy appear to be the underlying mechanisms of Cu NP toxicity in lung cells. In vivo studies on the lung toxicity of CuO NPs are largely lacking. Some studies have shown that intratracheal instillation of CuO NPs induced oxidative stress, inflammation and neoplastic lesions in rats. This review critically assessed the current findings of the toxicity of CuO NPs in the lung.
- 130Sandhya Rani, V.; Kishore Kumar, A.; Kumar, C. P.; Rama Narsimha Reddy, A. Pulmonary Toxicity of Copper Oxide (CuO) Nanoparticles in Rats. J. Med. Sci. 2013, 13 (7), 571– 577, DOI: 10.3923/jms.2013.571.577There is no corresponding record for this reference.
- 131Huang, Y. C.; Vieira, A.; Huang, K. L.; Yeh, M. K.; Chiang, C. H. Pulmonary Inflammation Caused by Chitosan Microparticles. J. Biomed. Mater. Res., Part A 2005, 75A (2), 283– 287, DOI: 10.1002/jbm.a.30421129Pulmonary inflammation caused by chitosan microparticlesHuang, Y. C.; Vieira, A.; Huang, K. L.; Yeh, M. K.; Chiang, C. H.Journal of Biomedical Materials Research, Part A (2005), 75A (2), 283-287CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Chitosan is a cationic biopolymer derived from chitin with potential therapeutic applications such as controlled drug delivery to mucosal-epithelial surfaces in the body. Inhaled chitosan microparticles (CM), for example, are of potential interest in pulmonary pharmacotherapy. In this context, the authors examine some basic reactions of lung tissue to CM. Inhaled CM (2-10 mg/kg of particles) induce dose-dependent proinflammatory effects in rat lungs; these effects are documented in increases in bronchoalveolar lavage fluid protein (BALF-P) and lactate dehydrogenase activity (BALF-LDH) and increases in lung tissue myeloperoxidase (MPO) activity and leukocyte migration. Overall, the biochem. parameters (i.e., av. of BALF-P, BALF-DH, and MPO) indicate that the inflammation response is 1.8-fold greater than controls without CM; the same inflammation parameters, however, are 1.9-fold lower with CM compared with the proinflammatory effects of lipopolysaccharide (LPS). Cytol. examn. of BALF shows a large infiltration of polymorphonuclear neutrophils to lung tissue: more than a 6-fold increase in this population of inflammatory cells, after inhalation of CM relative to air inhalation controls. Thus, the results indicate that inhaled CM can have significant proinflammatory effects on lung tissues; these effects are mild relative to LPS but need to be considered in the context of therapeutic applications via pulmonary delivery if such concns. of CM are used.
- 132Worthington, K. L. S.; Adamcakova-Dodd, A.; Wongrakpanich, A.; Mudunkotuwa, I. A.; Mapuskar, K. A.; Joshi, V. B.; Allan Guymon, C.; Spitz, D. R.; Grassian, V. H.; Thorne, P. S.; Salem, A. K. Chitosan Coating of Copper Nanoparticles Reduces in Vitro Toxicity and Increases Inflammation in the Lung. Nanotechnology 2013, 24 (39), 395101, DOI: 10.1088/0957-4484/24/39/395101130Chitosan coating of copper nanoparticles reduces in vitro toxicity and increases inflammation in the lungWorthington, Kristan L. S.; Adamcakova-Dodd, Andrea; Wongrakpanich, Amaraporn; Mudunkotuwa, Imali A.; Mapuskar, Kranti A.; Joshi, Vijaya B.; Guymon, C. Allan; Spitz, Douglas R.; Grassian, Vicki H.; Thorne, Peter S.; Salem, Aliasger K.Nanotechnology (2013), 24 (39), 395101/1-395101/10, 10 pp.CODEN: NNOTER; ISSN:1361-6528. (IOP Publishing Ltd.)Despite their potential for a variety of applications, copper nanoparticles induce very strong inflammatory responses and cellular toxicity following aerosolized delivery. Coating metallic nanoparticles with polysaccharides, such as biocompatible and antimicrobial chitosan, has the potential to reduce this toxicity. In this study, copper nanoparticles were coated with chitosan using a newly developed and facile method. The presence of coating was confirmed using XPS, rhodamine tagging of chitosan followed by confocal fluorescence imaging of coated particles and obsd. increases in particle size and zeta potential. Further phys. and chem. characteristics were evaluated using dissoln. and x-ray diffraction studies. The chitosan coating was shown to significantly reduce the toxicity of copper nanoparticles after 24 and 52 h and the generation of reactive oxygen species as assayed by DHE oxidn. after 24 h in vitro. Conversely, inflammatory response, measured using the no. of white blood cells, total protein, and cytokines/chemokines in the bronchoalveolar fluid of mice exposed to chitosan coated vs. uncoated copper nanoparticles, was shown to increase, as was the concn. of copper ions. These results suggest that coating metal nanoparticles with mucoadhesive polysaccharides (e.g. chitosan) could increase their potential for use in controlled release of copper ions to cells, but will result in a higher inflammatory response if administered via the lung.
- 133Cassano, D.; Summa, M.; Pocovi-Martinez, S.; Mapanao, A.-K.; Catelani, T.; Bertorelli, R.; Voliani, V. Biodegradable ultrasmall-in-nano gold architectures: mid-period in vivo biodistribution and excretion assessment. Particle and Particle Systems Characterization 2019, 36, 1800464, DOI: 10.1002/ppsc.201800464There is no corresponding record for this reference.
- 134Vlamidis, Y.; Voliani, V. Bringing again noble metal nanoparticles to the forefront of cancer therapy. Front. Bioeng. Biotechnol. 2018, 6 DOI: 10.3389/fbioe.2018.00143 .There is no corresponding record for this reference.
- 135Santi, M.; Maccari, G.; Mereghetti, P.; Voliani, V.; Rocchiccioli, S.; Ucciferri, N.; Luin, S.; Signore, G. Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization. Bioconjugate Chem. 2017, 28 (2), 471– 480, DOI: 10.1021/acs.bioconjchem.6b00611131Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle InternalizationSanti, Melissa; Maccari, Giuseppe; Mereghetti, Paolo; Voliani, Valerio; Rocchiccioli, Silvia; Ucciferri, Nadia; Luin, Stefano; Signore, GiovanniBioconjugate Chemistry (2017), 28 (2), 471-480CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chem. derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quant. structure-activity and relationship (QSAR) anal. and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.
- 136Barbero, F.; Russo, L.; Vitali, M.; Piella, J.; Salvo, I.; Borrajo, M. L.; Busquets-Fité, M.; Grandori, R.; Bastús, N. G.; Casals, E.; Puntes, V. Formation of the Protein Corona: The Interface between Nanoparticles and the Immune System. Semin. Immunol. 2017, 34, 52– 60, DOI: 10.1016/j.smim.2017.10.001132Formation of the protein corona: the interface between nanoparticles and the immune systemBarbero, Francesco; Russo, Lorenzo; Vitali, Michele; Piella, Jordi; Salvo, Ignacio; Borrajo, Mireya L.; Busquets-Fite, Marti; Grandori, Rita; Bastus, Neus G.; Casals, Eudald; Puntes, VictorSeminars in Immunology (2017), 34 (), 52-60CODEN: SEIME2; ISSN:1044-5323. (Elsevier Ltd.)The interaction of inorg. nanoparticles and many biol. fluids often withstands the formation of a Protein Corona enveloping the nanoparticle. This Protein Corona provides the biol. identity to the nanoparticle that the immune system will detect. The formation of this Protein Corona depends not only on the compn. of the nanoparticle, its size, shape, surface state and exposure time, but also on the type of media, nanoparticle to protein ratio and the presence of ions and other mol. species that interfere in the interaction between proteins and nanoparticles. This has important implications on immune safety, biocompatibility and the use of nanoparticles in medicine.
- 137Nienhaus, K.; Nienhaus, G. U. Protein Corona around Nanoparticles—Recent Advances and Persisting Challenges. Curr. Opin. Biomed. Eng. 2019, 10, 11– 22, DOI: 10.1016/j.cobme.2019.01.002There is no corresponding record for this reference.
- 138Akhuli, A.; Chakraborty, D.; Agrawal, A. K.; Sarkar, M. Probing the Interaction of Bovine Serum Albumin with Copper Nanoclusters: Realization of Binding Pathway Different from Protein Corona. Langmuir 2021, 37, 1823, DOI: 10.1021/acs.langmuir.0c03176134Probing the Interaction of Bovine Serum Albumin with Copper Nanoclusters: Realization of Binding Pathway Different from Protein CoronaAkhuli, Amit; Chakraborty, Debabrata; Agrawal, Aman Kumar; Sarkar, MoloyLangmuir (2021), 37 (5), 1823-1837CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)With an aim to understand the interaction mechanism of bovine serum albumin (BSA) with copper nanoclusters (CuNCs), three different types CuNCs having chem. different surface ligands, namely, tannic acid (TA), chitosan, and cysteine (Cys), have been fabricated, and investigations are carried out in the absence and presence of protein (BSA) at ensemble-averaged and single-mol. levels. The CuNCs, capped with different surface ligands, are consciously chosen so that the role of surface ligands in the overall protein-NCs interactions is clearly understood, but, more importantly, to find whether these CuNCs can interact with protein in a new pathway without forming the "protein corona", which otherwise has been obsd. in relatively larger nanoparticles when they are exposed to biol. fluids. Anal. of the data obtained from fluorescence, ζ-potential, and ITC measurements has clearly indicated that the BSA protein in the presence of CuNCs does not attain the binding stoichiometry (BSA/CuNCs > 1) that is required for the formation of "protein corona". This conclusion is further substantiated by the outcome of the fluorescence correlation spectroscopy (FCS) study. Further anal. of data and thermodn. calcns. have revealed that the surface ligands of the CuNCs play an important role in the protein-NCs binding events, and they can alter the mode and thermodn. of the process. Specifically, the data have demonstrated that the binding of BSA with TA-CuNCs and Chitosan-CuNCs follows two types of binding modes; however, the same with Cys-CuNCs goes through only one type of binding mode. CD (CD) measurements have indicated that the basic structure of BSA remains almost unaltered in the presence of CuNCs. The outcome of the present study is expected to encourage and enable better application of NCs in biol. applications.