đánh giá khả năng diệt khuẩn nano đối với sức khỏe của con người

REVIEW PAPER A review of the antibacterial effects of silver nanomaterials and potential implications for human health and the environment Catalina Marambio-Jones • Eric M. V. Hoek Received: 29 July 2009 / Accepted: 6 March 2010 / Published online: 23 March 2010 Ó Springer Science+Business Media B.V. 2010 Abstract Here, we present a review of the antibacterial effects of silver nanomaterials, including proposed antibacterial mechanisms and possible toxicity to higher organisms. For purpose of this review, silver nanomaterials include silver nanoparticles, stabilized silver salts,silver–dendrimer, polymer and metal oxide composites, and silver-impregnated zeolite and activated carbon materials. While there is some evidence that silver nanoparticles can directly damage bacteria cell membranes, silver nanomaterials appear to exert bacteriocidal activity predominantly through release of silver ions followed (individually or in combination) by increased membrane permeability, loss of the proton motive force, inducing de-energization of the cells and efflux of phosphate, leakage of cellular content, and disruption DNA replication. Eukaryotic cells could be similarly impacted by most of these mechanisms and, indeed, a small but growing body of literature supports this concern. Most antimicrobial studies are performed in simple aquatic media or cell culture media without proper characterization of silver nanomaterial stability (aggregation, dissolution, and re-precipitation). Silver nanoparticle stability is governed by particle size, shape, and capping agents as well as solution pH, ionic strength, specific ions and ligands, and organic macromolecules—all of which influence silver nanoparticle stability and bioavailabil- ity. Although none of the studies reviewed definitively proved any immediate impacts to human health or the environment by a silver nanomaterial containing product, the entirety of the science reviewed suggests some caution and further research are warranted given the already widespread and rapidly growing use of silver nanomaterials. Keywords Silver Á Nanoparticle Á Antimicrobial Á Antibacterial Á Nanotechnology Á Nanotoxicology Á Safety Á EHS Introduction The broad-spectrum antimicrobial properties of silver encourage its use in biomedical applications, water and air purification, food production, cosmetics, clothing, and numerous household products. With the rapid development of nanotechnology, applications have been extended further and now silver is the engineered nanomaterial most commonly used in consumer products (Rejeski 2009). Clothing, respi- rators, household water filters, contraconceptives, antibacterial sprays, cosmetics, detergent, dietary supplements, cutting boards, sox, shoes, cell phones, laptop keyboards, and children’s toys are among the C. Marambio-Jones Á E. M. V. Hoek (&) Department of Civil and Environmental Engineering, California NanoSystems Institute, University of California, Los Angeles, 5732G Boelter Hall, PO Box 951593, Los Angeles, CA 90095-1593, USA e-mail: emvhoek@ucla.edu 123 J Nanopart Res (2010) 12:1531–1551 DOI 10.1007/s11051-010-9900-y retail products that purportedly exploit the antimicrobial properties of silver nanomaterials. Different forms of silver nanomaterials already in such products include: metallic silver nanoparticles (Arora et al. 2008; Chi et al. 2009; Choi et al. 2008; Hwang et al. 2008; Kim et al. 2007, 2008a, b; Kvitek et al. 2008; Lok et al. 2006; Raffi et al. 2008; Schrand et al. 2008; Sondi and Salopek-Sondi 2004; Vertelov et al. 2008), silver chloride particles (Choi et al. 2008), silver-impregnated zeolite powders and activated carbon materials (Cowan et al. 2003; Inoue et al. 2002; Yoon et al. 2008a, b), dendrimer–silver complexes and composites (Balogh et al. 2001; Lesniak et al. 2005; Zhang et al. 2008), polymer- silver nanoparticle composites (Bajpai et al. 2007; Damm and Munstedt 2008; Damm et al. 2008; Hlidek et al. 2008; Jin et al. 2007; Kim et al. 2009a, b; Kvitek et al. 2008; Naidu et al. 2008;Nita2008; Sambhy and Sen 2008; Sanpui et al. 2008; Xu et al. 2006), silver-titanium dioxide composite nanopowders (Yeo and Kang 2008), and silver nanoparticles coated onto polymers like polyurethane (Jain and Pradeep 2005). While all of these forms of silver exert antimicrobial activity to some extent through release of silver ions, silver nanoparticles might exhibit additional antimicrobial capabilities not exerted by bulk or ionic silver (Chen and Schluesener 2008). Already, silver nanoparticles have been shown to be effective biocides against: (a) bacteria such as Escherichia coli, Staphylococcus aureus , Staphylo- coccus epidermis, Leuconostoc mesenteroides, Bacil- lus subtilis, Klebsiella mobilis, and Klebsiella pneumonia among others (Benn and Westerhoff 2008; Chen and Chiang 2008; Falletta et al. 2008; Hernandez-Sierra et al. 2008; Ingle et al. 2008; Jung et al. 2009; Kim 2007; Kim et al. 2007, 2009a, b; Kvitek et al. 2008; Raffi et al. 2008; Ruparelia et al. 2008; Smetana et al. 2008; Sondi and Salopek-Sondi 2004; Vertelov et al. 2008; Yang et al. 2009; Yoon et al. 2008a, b); (b) fungi such as Aspergillus niger, Candida albicans, Saccharomyces cerevisia, Tricho- phyton mentagrophytes, and Penicillium citrinum (Kim et al. 2007, 2008a, b, 2009a, b; Roe et al. 2008; Vertelov et al. 2008; Zhang et al. 2008); and (c) virii such as Hepatitis B, HIV-1, syncytial virus (Elechiguerra et al. 2005; Lu et al. 2008; Sun et al. 2008; Zodrow et al. 2009). Hybrid silver nanocomposites with dendrimers and polymers have been shown effective for S. aureus, Pseudomonas aeruginosa, E. coli , B. subtilis, and K. mobilis (Balogh et al. 2001; Zhang et al. 2008). Furthermore, silver loaded in nanoporous materials such as silver- exchanged zeolites exhibit antibacterial effects for Pseudomonas putida, E. coli, B. subtilis, S. aureus, and P. aeruginosa (Cowan et al. 2003; Inoue et al. 2002; Lind et al. 2009; McDonnell et al. 2005). Despite the vast number of papers touting the beneficial antimicrobial effects of silver nanomaterials, a relatively modest number of studies have attempted to elucidate the mechanisms by which silver nanomaterials exert this antimicrobial activity. As a result, the mechanisms are not widely understood or agreed upon. For bacteria, commonly proposed mechanisms in the literature begin with the release of silver ions (Hwang et al. 2008; Smetana et al. 2008) followed by generation of reactive oxygen species (ROS) (Hwang et al. 2008; Kim et al. 2007) and cell membrane damage (Choi et al. 2008; Raffi et al. 2008; Smetana et al. 2008; Sondi and Salopek-Sondi 2004), but there are many contradictory findings reported. The more widespread our use of silver nanomaterials becomes the more widespread will become the potential for human and ecosystem exposure. Silver nanoparticles may be released to the environment from discharges at the point of production, from erosion of engineered materials in household products (e.g., antibacterial coatings and silver-impregnated water filters), and from washing or disposal of silver-containing products (Benn and Westerhoff 2008). Silver released to both natural and engineered systems will likely impact the lowest trophic levels first, i.e., bacteria. However, little is known about trophic transfer of silver and impacts to higher organisms. Indeed, silver nanoparticles have already been proven toxic to both aerobic and anaerobic bacteria isolated from wastewater treatment plants (Choi and Hu 2008), which we speculate could lead to severe disruption of this critical environmental infrastructure if the load of silver into wastewater treatment plants increases significantly. Given the vast number of products leveraging the benefits of silver, it seems prudent to assess the potential human and ecosystem hazards associated with its increased utilization. The main routes of human exposure would be the respiratory system, gastrointestinal system, and skin, which are interfaces 1532 J Nanopart Res (2010) 12:1531–1551 123 between the internal systems of the human body and the external environment (Chen and Schluesener 2008). For example, silver nanomaterials may enter through the respiratory tract due to inhalation of dust or fumes containing silver nanomaterials at the point of manufacture, it may be ingested from water, children’s toys, or food containers treated with silver, or it may penetrate the skin via silver-containing textiles and cosmetics. Additionally, other potential entryways could include the female genital tract (due to incorporation of silver nanoparticles into numerous female hygienic products), via systemic administra- tion as it is used for some imaging and therapeutic purposes (Chen and Schluesener 2008; Schrand et al. 2008; West and Halas 2003), or by incorporation into medical implants, catheters, and wound dressings (Furno et al. 2004; Galiano et al. 2008; Maneerung et al. 2008; Roe et al. 2008). In addition to broad-spectrum antimicrobial effects, silver nanoparticles have produced toxic effects in higher cell lines like zebra fish, clams, rats, and humans (Arora et al. 2008, 2009; Asharani et al. 2008; Braydich-Stolle et al. 2005; Hsin et al. 2008; Hussain et al. 2005; Kim et al. 2008a, b; Sung et al. 2008; Yeo and Kang 2008; Yeo and Yoon 2009). Evidence in rodents shows that after entering into the body silver nanoparticles can accumulate and, in some cases, damage tissues such as the liver, lungs, and olfactory bulbs, or penetrate the blood– brain barrier (Arora et al. 2009; Braydich-Stolle et al. 2005; Hussain et al. 2005; Sung et al. 2008). A study in human cells concluded that silver can be genotoxic (Asharani et al. 2009). Additionally, a release of ionic silver led to the sterility of Macoma balthica clams in the San Francisco Bay during the 1980s (Brown et al. 2003). If silver nanomaterials exhibit similar or stronger reactivity, the impacts of this isolated event in San Francisco may foreshadow potential ecosystem impacts of silver nanomaterials. The various forms of silver nanomaterials are among the most promising antimicrobial agents being developed from nanotechnology, but the preliminary evidence of effects on higher organisms alerts us to remain cautious of its widespread utilization. This cautiousness demands additional research to deter- mine how to safely design, use, and dispose products containing silver nanomaterials without creating new risks to humans or the environment. Consequently, the goal of this article is to provide a critical review of the state-of-knowledge about silver nanomaterial antibacterial effects with insights toward better understanding potential implications for human health and the environment. Typical forms of silver nanomaterials Herein, the term ‘‘silver nanomaterials’’ refers to any silver-containing materials with enhanced activity due to their nanoscale features. In some cases, commercial products containing metallic silver nanoparticles in the range of 5–50 nm or ionic silver are given the name ‘nanosilver’ (Panyala et al. 2008). Silver nanoparticles are nanoscale clusters of metallic silver atoms, Ag 0 , engineered for some practical purpose—most typically antimicrobial and sterile applications. The most common method of producing silver nanoparticles is chemical reduction of a silver salt dissolved in water with a reducing compound such as NaBH 4 , citrate, glucose, hydrazine, and ascorbate (Gulrajani et al. 2008; Martinez-Castanon et al. 2009; Panacek et al. 2006; Pillai and Kamat 2004). Strong reductants lead to small monodisperse particles, while generating larger sizes can be difficult to control. Weaker reductants produce slower reduction reactions, but the nanoparticles obtained tend to be more polydisperse in size. In order to generate silver nanoparticles with controlled sizes, a two-step method is usually utilized. In this method, nuclei particles are prepared using a strong reducing agent and they are enlarged by a weak reducing agent (Schneider et al. 1994; Shirtcliffe et al. 1999). Since reducing agents for silver nanoparticle synthesis are often considered toxic or hazardous, the use of green synthesis methods is becoming a priority (Panacek et al. 2006). A recent review of green synthesis methods for silver nanoparticles discussed the use of polysaccharides, polyphenols, Tollens agent, irradiation, biological reduction, and polyoxometalate (Sharma et al. 2009). Polysaccharides and polyphenols are typically used as capping agents during silver nanoparticle synthesis, but they may also contribute to reduction of silver ions through as yet poorly understood mechanisms. For polysaccharides, the reduction of silver may be linked to the oxidation of aldehyde groups to carboxylic acid groups (Manzi and van J Nanopart Res (2010) 12:1531–1551 1533 123 Halbeek 1999). Typical polysaccharides used are glucose, starch, and heparin (Batabyal et al. 2007; Huang and Yang 2004; Manno et al. 2008; Singh et al. 2009; Venediktov and Padokhin 2008). In the Tollens method, a silver ammoniacal solution is reduced by an aldehyde forming silver nanoparticles. This method can be altered (i.e., ‘‘modified Tollens method’’) by reducing Ag ? using saccharides in the presence of ammonia resulting in films with nanoparticles sizes ranging from 50 to 200 nm and silver hydrosols ranging from 20 to 50 nm (Panacek et al. 2006; Saito et al. 2003; Yu and Yam 2004). Silver nanoparticles can also be synthesized by irradiating silver salts solutions containing reducing and capping agents. Different sources of irradiation have been used such as laser, microwave, ionization radiation, and radiolysis (Abid et al. 2002; Ha et al. 2006;Li et al. 2006; Long et al. 2007; Mahapatra et al. 2007; Pillai and Kamat 2004; Sharma et al. 2007, 2008; Yanagihara et al. 2001; Yin et al. 2004; Zeng et al. 2007). Biological methods involve the production of silver nanoparticles utilizing extracts from bio-organisms as reductant, capping agents or both (Li et al. 2007; Sanghi and Verma 2009). Such extracts can include proteins, amino acids, polysaccharides, and vitamins (Eby et al. 2009; Sharma et al. 2009). Plant extracts such as apiin (a glucoside compound) and leaf extract from magnolia, Persimmon, geranium, and Pine leaf have also been used as reducing agents of Ag ? to produce silver nanoparticles (Kasthuri et al. 2009; Shankar et al. 2003; Song and Kim 2009). Additionally, silver nanoparticles can be synthesized by several microorganisms such as the bacterial strains Bacillus licheniformis, K. pneumonia, and fungi strains such as Verticillium and Fusarium oxysporum, Aspergillus flavus (Ahmad et al. 2003; Kalishwaralal et al. 2008; Mokhtari et al. 2009; Mukherjee et al. 2001; Senapati et al. 2004; Vig- neshwaran et al. 2007). It is not clear if these microbes are impacted (favorably or unfavorably) by exposure to engineered forms of nano-scaled silver, but their seemingly favorable interactions with silver suggest resistance may be fairly widespread. Another procedure utilized to synthesize silver nanoparticles is the solvated metal atom dispersion (SMAD) method (Stoeva et al. 2002). In this method, a metal is co-vaporized with a solvent onto a liquid nitrogen cooled surface, as liquid nitrogen is removed the metal atoms and solvent warms causing the aggregation of metal atoms. SMAD can be performed in conjunction with digestive ripening, in this way the nanoparticles resulting from SMAD method are further refined by heating them in inert atmosphere in the presence of selected ligands that encourage the particles to reach a narrow size range. As a result, monodisperse spherical particles are obtained (Sme- tana et al. 2005, 2008). The use of silver ions as antimicrobial agents is limited by the solubility of silver ions in biological and environmental media containing Cl - , because AgCl has a very low solubility and rapidly precip- itates out of solution. In some cases, silver salts are stabilized with hyperbranched polymers or dendrimers that act as nanoreactors, wherein silver ions are initially complexed with a specific moiety in the polymeric structure and then reduced to form silver nanoparticles within the polymeric matrix (Fig. 1) (Lesniak et al. 2005; Zhang et al. 2008). Dendri- mer–silver complexes prevent silver ions from precipitating and keep silver dispersed in the media long enough to be delivered where it is desired (Balogh et al. 2001; Lesniak et al. 2005; Zhang et al. 2008). Silver ions can also be stabilized in zeolite channels (Fig. 2) or deposited in activated carbon fibers (Inoue et al. 2002; Ogden et al. 1999; Pal et al. 2009). Composites of silver coatings over titanium dioxide nanoparticles are used in products such as baby bottles and blood-clotting agents to produce antibacterial activity (Yeo and Kang 2008). Other hybrid silver nanomaterials may include silver nanoparticles coated onto polyurethane and silver–magnetite composite nanoparticles (Fe 3 O 4 @Ag); both of these hybrids are utilized for water disinfection (Gong et al. 2007; Jain and Pradeep 2005). One of the challenges of using silver (or any) nanoparticles for water treatment is recovering the particles after the treatment process. Silver–magnetite nanoparticles offer the potential advantage of being removed by a magnet, avoiding release to the environment, and making possible direct reuse without additional separation processes. For example, in related research, magnetite particles proved effective for removal of arsenic from water (Mayo et al. 2007; Yavuz et al. 2006). However, for silver materials, an additional concern is controlling the release of metal ions into the final produce water. 1534 J Nanopart Res (2010) 12:1531–1551 123 Evidence of silver toxicity in microbes and higher organisms Here, toxicity refers to any deleterious effects on an organism upon exposure to silver. Obviously, if the practical intent is to disinfect or sterilize a specific type of organism, then toxicity may be interpreted as a positive outcome (e.g., antibacterial, antiviral, etc.). However, if the same material exerts unin- tended or undesired impacts to other organisms, then such toxicity may be interpreted as a potential hazard. Evidence of toxicity to bacteria Table 1 presents a concise summary of silver nanomaterial antibacterial studies. Kim et al. reported that 13.4-nm silver nanoparticles prepared by reduction of silver nitrate with sodium borohydride show mini- mum inhibitory concentration (MIC) against E. coli below 6.6 nM and above 33 nM for S. aureus (Kim et al. 2007). In another study, 16-nm silver nanoparticles generated by gas condensation were able to completely inhibit colony forming units (CFU) ability of E. coli at 60 lg/mL (Raffi et al. 2008). Fig. 1 General formation scheme of PAMAM dendrimer complexes and nanocomposites. PAMAM structural subunits: core = ethylenediamine, branching site = –N\, chains connecting the branching sites = –CH 2 CH 2 CONHCH 2 CH 2 –. Terminal groups on the surface are marked as –CH 2 CH 2 –CO–Z. Silver ions (represented by M ? ) can be pre-organize and subsequently contained in the form of solubilized and stabilize, high-surface area silver domains. Redrawn based on (Balogh et al. 2001) Fig. 2 Silver ions stabilized in zeolite channels and ionic exchange of silver ions with other cations in the media. Left picture shows zeolite type A and right picture shows zeolite type X. Adapted from (Auerbach 2003) J Nanopart Res (2010) 12:1531–1551 1535 123 Commercially available silver nanopowders at a concentration of 300 lg/mL and SMAD-produced silver nanoparticles at a concentration of 30 lg/mL were able to reduce (after 10 min contact time) colony forming units of E. coli and S. aureus from 2 9 10 4 CFU/mL to 0 and \20, respectively (Smetana et al. 2008). Additionally, MICs ranging from 13.5 to 1.69 lg/mL were reported for bacterial strains such as S. aureus CCM 3953, Enterococcus faecalis CCM 4224, E. coli CCM 3954, and P. aeruginosa CCM 3955, and for strains isolated from human clinical material like P. aeruginosa, methicillin-susceptible S. epidermidis, methicillin-resistant S. epidermidis, methicillin-resistant S. aureus, vancomycin-resistant Enterococcus faecium, and K. pneumonia when exposed to 26-nm silver nanoparticles prepared by the reduction of [Ag(NH 3 ) 2 ] ? with D-maltose (Kvitek et al. 2008). Silver nanoparticles also produced 76% reduction of B. subtilis CFU after applying silver nanoparticles with a size distribution from 14 to 710 nm in an aerosol form (Yoon et al. 2008a, b). Likewise, silver nanoparticles are effective against E. coli, S. aureus, and L. mesenteroides. Also, 10-nm Myramistin Ò stabilized silver nanoparticles inhibit growth of E. coli and S. aureus at 2.5 lg/mL and L. mesenteroides at 5 lg/mL (Vertelov et al. 2008). Table 1 Bactericidal activity of nano-scaled silver and silver loaded in zeolite Silver form Size data Bacterial strain Key aspects References Silver nanoparticles/ nano-sized silver powders 13.4 nm b E. coli, S. aureus Minimal inhibition concentration against E. coli was lower than 6.6 nM and higher than 33 nM for S. aureus (Kim et al. 2007) 16 nm E. coli Complete inhibition of CFU ability at 60 lg/mL (Raffi et al. 2008) 1 lm E. coli, S. aureus CFU reduced by 4 to 5 log units (Smetana et al. 2008) 26 nm Standard strains and strains isolated from clinical material Minimal inhibition concentration from 1.69 to 13.5 lg/mL (Kvitek et al. 2008) 10 nm a E. coli, S. aureus Growth inhibition achieved at 5 lg/mL (Vertelov et al. 2008) L. mesenteroides Growth inhibition achieved at 2.5 lg/mL Silver nanoparticles applied as aerosol 14.1–710 nm c B. subtilis 76% CFU reduction by applying silver nanoparticles aerosol on B. subtilis aerosol (Yoon et al. 2008a, b) Silver nanoparticles stabilized in hyperbranched polymers 1.4–7.1 nm b E. coli, S. aureus, B. subtilis, K. mobilis Microbial activity increases as silver content in polymer decreases since decrease in silver nanoparticle size (Zhang et al. 2008) Silver–dendrimer complexes and nanocomposites S. aureus, P. aeruginosa, E. coli Antimicrobial activity was comparable or higher to those of silver nitrate solutions. The activity and solubility did not decrease even in presence of sulfate or chloride ions (Balogh et al. 2001) Silver zeolite E. coli CFU reduced by 7 log units in 5 min (Inoue et al. 2002) Zeolite containing silver and zinc E. coli Minimal bactericidal concentration of 78 lg/mL (as Ag?) for bacteria grown is Luria- Bertani broth (Cowan et al. 2003) E. coli, S. aureus, P. aeruginosa Minimal bactericidal concentration of 39 lg/mL (as Ag?) for bacteria grown is Tryptic Soy broth Note: Size measured by a dynamic light scattering, b TEM images, and c scanning mobility particle sizer 1536 J Nanopart Res (2010) 12:1531–1551 123 Dendrimer–silver nanocomposites have also been proven effective antibacterials. For example, poly(amidoamine) dendrimer–silver composites have been used against S. aureus, P. aeruginosa, E. coli, B. subtilis, and K. mobilis (Balogh et al. 2001; Zhang et al. 2008). Additionally, silver ions loaded in zeolites elicit antibacterial properties. Two recent studies demonstrated 7 log reduction in CFUs for E. coli, from an initial concentration of 10 7 CFU/cm 3 , after 5 min of contact time with 333.3 lg/mL of Ag-loaded zeolite (Inoue et al. 2002), and MICs of 78 lgAg ? /mL for E. coli and 39 lgAg ? /mL for S. aureus and P. aeruginosa, plus some bactericidal activity against Listeria monocytogenes (Cowan et al. 2003). Evidence of toxicity to other microorganisms Silver nanoparticles also inactivate fungi, virii, and algae (Table 2). For example, silver nanoparticles of sizes ranging from 1.4 to 7.1 nm and stabilized in Table 2 Summary of silver nanoparticles toxicity to other microorganisms Strain Silver nanoparticles Size (nm) Key aspects Reference Fungi A. niger Myramistin Ò stabilized silver nanoparticles 10 a MIC were found to be 5 mg/L (Vertelov et al. 2008) Silver nanoparticles stabilized in hyper branched polymers 1.4–7.1 b Formation of inhibition zones around silver nanoparticles inoculated spots in agar plates (Zhang et al. 2008) S. cerevisiae Myramistin Ò stabilized silver nanoparticles 10 a MIC were found to be 5 mg/L (Vertelov et al. 2008) T. mentagrophytes Silver nanoparticles 3 b IC 80 between 1 and 4 mg/L (Kim et al. 2008a, b) C. Albanicas Silver nanoparticles 3 b Silver nanoparticles inhibited micelial formation, which is responsible for pathogenicity (Kim et al. 2008a, b) Silver nanoparticles 3 b Antifungal activity may be exerted by cell membrane structure disruption and inhibition of normal budding process (Kim et al. 2009a, b) Silver nanoparticles coated on plastic catheters 3–18 b Catheter coated with silver nanoparticles inhibited growth and biofilm formation. (Roe et al. 2008) Yeast (isolated from bovine mastitis) Silver nanoparticles 13.4 b MIC estimated between 6.6 nM and 13.2 nM (Kim et al. 2007) P. citrinum Silver nanoparticles stabilized in hyper branched polymers 1.4–7.1 b Formation of inhibition zones around silver nanoparticles inoculated spots in agar plates (Zhang et al. 2008) Viruses Hepatitis B virus Silver nanoparticles 10 b Inhibition of virus replication (Lu et al. 2008) HIV-1 Silver nanoparticles 16.19 ± 8.68 b Only 1–10 nm nanoparticles attached to virus restraining virus from attaching to host cells. (Elechiguerra et al. 2005) Syncitial virus Silver nanoparticles 44% inhibition of Syncitial virus infection (Sun et al. 2008) Algae C. reinhardtii Silver nanoparticles 10–200 a EC 50 for the photosynthetic yield was found in 0.35 mg/L of total silver content after 1 h of exposure (Navarro et al. 2008) Note: Size measured by a dynamic light scattering and b TEM images J Nanopart Res (2010) 12:1531–1551 1537 123 hyperbranched polymers, and silver nanoparticles stabilized with Myramistin Ò (size 10 nm) inhibited the growth of A. niger (Tomsic et al. 2009; Vertelov et al. 2008; Zhang et al. 2008); the same Myramistin Ò stabilized particles were found toxic toward S. cerevisiae showing a MIC of 5 mg/L. Further, 3-nm silver nanoparticles showed IC 80 values from 1 to 4 lg/mL against T. mentagrophytes and 2 to 4 lg/mL for C. albanicans (Kim et al. 2008a, b); while in other study, it was reported that the antifungal activity of silver nanoparticles against C. albanicans could be exerted by cell membrane structure disruption leading to reproduction inhibition (Kim et al. 2009a, b). Addi- tionally, silver nanoparticles (sizes ranging from 3 to 18 nm) coated in catheters were able to inhibit growth of C. albicans. Although, in this case, no analysis of the antifungal molecular mechanism was done, the authors speculate that silver ions (Ag ? ) released from the matrix were the antifungal agents (Kim et al. 2008a, b, 2009a, b; Roe et al. 2008). Furthermore, silver nanoparticles suppress yeast growth and show MIC between 6.6 and 13.2 nM (Kim et al. 2007). Silver nanoparticles of sizes from 1.4 to 7.1 nm and stabilized in hyperbranched polymers (HPAMAM- N(CH3)2/AgNPs composite) inhibit P. citrinum growth (Zhang et al. 2008). Although information about toxicity for algae is limited, silver nanoparticles reduced the photosynthetic yield of Chlamydomonas reinhardtii; in this case, the observed toxicity was attributed to Ag ? ions (Navarro et al. 2008). Evidence of virus inactivation is also reported in literature. For example, silver nanoparticles of 10 nm are able to inhibit hepatitis B virus replication (Lu et al. 2008). Additionally, PVP-coated silver nanoparticles in the range 1–10 nm attach to HIV-1 virus, inhibiting the virus from attaching to host cells (Elechiguerra et al. 2005). In other study, PVP-coated silver nanoparticles reduced respiratory syncytial virus infection by 44% (Sun et al. 2008). Polysulfone ultrafiltration membranes impregnated with silver nanoparticles of sizes ranging from 1 to 70 nm showed enhanced virus removal, thus improving water disinfection via low pressure membrane filtra- tion (Zodrow et al. 2009). Evidence of toxicity for mammalian cells Significant evidence has been reported in relation to the toxicity of silver nanoparticles to higher organisms. It has been shown toxic to fish such as zebrafish (Asharani et al. 2008; Yeo and Kang 2008; Yeo and Yoon 2009), Diptera species such as Drosophila melanogaster, known asfruit fly (Ahamed et al. 2010) and different mammalian cell lines of mice (Brayd- ich-Stolle et al. 2005; Hussain et al. 2005), rats (Kim et al. 2008a, b; Sung et al. 2008), and also humans (Asharani et al. 2009; Braydich-Stolle et al. 2005; Hsin et al. 2008; Hussain et al. 2005). This review presents only a few, brief examples of silver nanomaterial toxicity for mammalian cells (Table 3). More detailed, focused reviews on this topic are available elsewhere (Chen and Schluesener 2008; Panyala et al. 2008). Table 3 Evidence of nano-scaled silver toxicity for mammalian cells Target cell/organism Key aspects Reference Rat lung cells Reduction in lung function and inflammatory lesions (Sung et al. 2008) Sprague-Dawley rats Silver nanoparticles accumulation in olfactory bulb and subsequent translocation to the brain (Kim et al. 2008a, b) Mouse stem cells Cell leakage and reduction of mitochondrial function (Braydich-Stolle et al. 2005) Rat liver cells Cell leakage and reduction of mitochondrial function (Hussain et al. 2005) Human fibrosarcoma and human skin/carcinoma Oxidative stress. Low doses produced apoptosis and higher dose necrosis (Arora et al. 2008) Mouse fibroblast 50 lg/mL induced apoptosis to 43.4% of cells (Arora et al. 2009) Human colon cancer 100 lg/mL produced necrosis to 40.2% of cells Human glioblastoma Silver nanoparticles were found cytotoxic, genotoxic and antiproliferative (Asharani et al. 2009) Human fibroblast Silver nanoparticles were found cytotoxic, genotoxic and antiproliferative (Asharani et al. 2009) 1538 J Nanopart Res (2010) 12:1531–1551 123 Evidence of silver nanoparticle toxicity for mammalian cells was presented in the in vivo studies performed by Sung et al. (2008) and Kim et al. (2008a, b). In the former, a 90-day inhalation study in rats showed that silver nanoparticles reduce lung function and produce inflammatory lesions in the lungs. In the later, silver nanoparticles accumulated in the olfactory bulbs of Sprague-Dawley rats and also accumulated in the brain. Evidence from in vitro studies is alsoavailable in the literature. For example, silver nanoparticles have been shown to reduce mitochondrial function and to increase membrane leakage of mouse spermatogonial stem cell andrat liver cells (Braydich-Stolle etal. 2005; Hussain et al. 2005). Studies performed on human fibrosarcoma and human skin/carcinoma cells with silver nanoparticles used in a topical antimicrobial agent concluded that in the presence of the nanoparticles the cellular levels of glutathione are reduced, indicating oxidative stress, that results in cellular damage and lipid peroxidation (Arora et al. 2008). However, in the study performed by Arora et al. the dose required to induce apoptosis (0.78–1.56 lg/mL) was much smaller than that required to produce necrosis (12.5 lg/mL) in both cell types. Therefore, the authors concluded that, after the required in vivo studies, it would be possible to define a safe range for the application of silver nanoparticles as a topical antimicrobial agent. Similar differences of the required concentration to cause apoptosis or necrosis were found in a second study by the same authors in mouse fibroblasts and liver cells (Arora et al. 2009). In this second article, it was suggested that although silver nanoparticles may enter into the cells, the cellular antioxidant mechanisms would limit oxidative stress. Mechanistic studies of silver nanoparticle toxicity in mammalian cells have considered mouse fibroblast and human colon cancer cells (Hsin et al. 2008). In this study, silver nanoparticle doses of 50 lg/mL induced apoptosis to 43.4% of fibroblast cells, while 100 lg/mL produced necrosis to 40.2% of the cancer cells. The authors concluded that the apoptotic mechanisms in fibrosblast cells are a mitochondrial mediated pathway including the generation of ROS in the cell, which activate the apoptosis regulators JNK and p53 proteins inducing protein Bax to migrate to the surface of the mitochondria. That subsequently induces cytochrome C release from mitochondria and cleavage of PARP. Additionally, in a study done by Asharani, a possible mechanism of toxicity to human cells was proposed (Asharani et al. 2009). Silver nanoparticles would affect the mitochondrial respiratory chain, causing ROS generation and affecting the production of ATP, which subsequently leads to DNA damage. In this study, the authors also concluded that ‘‘even and small dose of Ag-NP (silver nanoparticles) has the potential to cause toxicity’’ and that silver nanoparticles are cytotoxic, genotoxic, and antiproliferative, being as toxic for human glioblastoma as for normal human fibroblasts cells. Mechanisms of silver’s antibacterial properties Although the mechanisms behind the activity of nano-scaled silver on bacteria are not yet fully elucidated, the three most common mechanisms of toxicity proposed to date are: (1) uptake of free silver ions followed by disruption of ATP production and DNA replication, (2) silver nanoparticle and silver ion generation of ROS, and (3) silver nanoparticle direct damage to cell membranes. The various observed and hypothesized interactions between silver nanomaterials and bacteria cells are conceptu- ally illustrated in Fig. 3. Fig. 3 Diagram summarizing nano-scaled silver interaction with bacterial cells. Nano-scaled silver may (1) release silver ions and generate ROS; (2) interact with membrane proteins affecting their correct function; (3) accumulate in the cell membrane affecting membrane permeability; and (4) enter into the cell where it can generate ROS, release silver ions, and affect DNA. Generated ROS may also affect DNA, cell membrane, and membrane proteins, and silver ion release will likely affect DNA and membrane proteins. Similar pictures have been published in (Damm et al. 2008; Neal 2008) J Nanopart Res (2010) 12:1531–1551 1539 123 Free silver ion uptake Silver nanoparticles have been reported to dissolve generating silver ions and it is thought that in vivo this release would be product of reactions of silver nanoparticles with H 2 O 2 (Asharani et al. 2009). Asharani has proposed the following reaction as a possible mechanism for silver nanoparticle oxidative dissolution. 2Ag þH 2 O 2 þ2H þ ! 2Ag þ þ2H 2 O E 0 ¼ 0:17 V: Asharani suggests that in eukaryotic cells this reaction could occur in the mitochondria, where exists an important concentration of H ? . Similarly, we hypothesized that a similar mechanism could occur in the bacterial cell membrane where proton motive force takes place. Another possible mechanism for the oxidative dissolution of silver nanoparticles has been reported by Choi et al., in this case silver is oxidized in the presence of oxygen. Choi et al. speculated that the observed changed of color of their silver nanoparticles suspensions, over a week period, would be attributed to this mechanism. 4Ag þO 2 þ 2H 2 O $ 4Ag þ þ 4OH À : The amount of free silver ion measured in this case was approximately 2.2% of the total silver content in the silver nanoparticle suspension (Choi et al. 2008). In other article, a 0.1% content of the total silver in partially oxidized silver nanoparticles suspensions was attributed to silver ions (Lok et al. 2007). Ionic silver has known antibacterial properties; thus, it is expected that eluted ions from silver nanoparticles are responsible for at least a part of their antibacterial properties. At sub-micromolar concentrations, Ag ? interacts with enzymes of the respiratory chain reaction such as NADH dehydro- genase resulting in the uncoupling of respiration from ATP synthesis. Silver ions also bind with transport proteins leading to proton leakage, inducing collapse of the proton motive force (Dibrov et al. 2002; Holt and Bard 2005; Lok et al. 2006). Silver inhibits the uptake of phosphate and causes the efflux of intracellular phosphate (Schreurs and Rosenberg 1982). The interaction with respiratory and transport proteins is due to the high affinity of Ag ? with thiol groups present in the cysteine residues of those proteins (Holt and Bard 2005; Liau et al. 1997; Petering 1976). Additionally, it has been reported that Ag ? increases DNA mutation frequencies during polymerase chain reactions (Yang et al. 2009). Bacterial cells exposed to milli-molar Ag ? doses suffer morphological changes such as cytoplasm shrink- age and detachment of cell wall membrane, DNA condensation and localization in an electron-light region in the center of the cell, and cell membrane degradation allowing leakage of intracellular contents (Feng et al. 2000;Jungetal.2008). Physiological changes occur together with the morphological changes. Bacterial cells enter an active, but non-culturable state in which physiological levels can be measured but bacteria are not able to growth and replicate. Several studies have linked the toxicity of silver nanoparticles to the release of silver ions. For example, Smetana et al. observed that silver ions eroded from high-surface area silver powders prepared by SMAD method interacted and destroyed bacterial cells (Sme- tana et al. 2008). In the same study, a second preparation of silver nanoparticles using water-soluble ligands was used to obtain silver nanoparticles with higher surface area to improve their antibacterial efficacy. However, the second preparation of silver nanoparticles showed lower toxicity toward bacterial cells than uncoated powders, suggesting the ligands prevented silver ion erosion; thus, diminishing the resulting toxicity. Another possible reason for this result is that the surface coatings prevented adhesion of silver nanoparticles to the bacterial cell surface, but the authors did not explore this option. Hwang et al. observed that Ag ? induced the same effect in bioluminescence bacteria sensitive to membrane protein damage and slightly less effect in a strain sensitive to superoxides compared to silver nanoparticles (Hwang et al. 2008). The authors suggested that silver nanoparticles produce silver ions that move inside the cell producing ROS through redox reactions with oxygen. In other research, bacterial activity of activated carbon fiber supported silver was attributed to the synergistic action of silver ions, superoxides, and hydrogen peroxide (Le Pape et al. 2004). Generation of reactive oxygen species Reactive oxygen species (ROS) are natural byprod- ucts of the metabolism of respiring organisms. While 1540 J Nanopart Res (2010) 12:1531–1551 123 [...]... reduce virusinduced cytopathic effect and plaque formation This study can contribute to the development of new antiviral nanomedicines [52] In vitro cytotoxicity experiments conducted on nanozeolites and monodisperse amorphous silica nanoparticles of similar size range (25–100 nm) and concentration (500 µg/ml) report lower toxicity in nanozeolites [53] The potential toxicity of organophyllosilicates on... success of nanometals in medicine highly relies on the transition from their risk assessment to risk elimination Researchers should consider a thorough investigation of nanoparticle concentration, distribution, sublethal cellular changes, cell type and experimental conditions of the cytotoxic assay; to overcome drawbacks associated with the applications of nanoparticles future science group Metallic nanoparticles... 62 S-f Shi, J-f Jia, X-k Guo et al Toxicity of iron oxide nanoparticles against osteoblasts J. Nanopart Res 14, 1091 (2012) 63 Lu J, Ma S, Sun J et al Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging Biomaterials 30, 2919–2928 (2009) 64 Derfus A Probing the cytotoxicity of semiconductor quantum dots Nano Lett 4, 11–18 (2004) 65 Hoshino A, Hanaki K, Suzuki... metallic nanoparticles The relationship of metallic nanoparticles with humans and the environment is greatly governed by their toxicity levels The amount of oxidative stress and free radicals released during their interaction with living tissues, and the concentration at which they are least destructive, are the points worth consideration before they are used for biomedical purposes Conclusion Nanometals... Aluminosilicate nanoparticles, when exposed to HeLa cells, are known to express toxicity depending on their size, composition, dose and shape Nanozeolites containing aluminum-like, ZSM-5, LTL and LTA, demonstrate a dose-dependent toxicity by inducing cell necrosis rather than cell apoptosis by the damnification for the cell membranes By contrast, pure silica nanozeolite silicalite-1 at the same concentration... single manganese-doped SPIO nanoparticle containing lipid–PEG micelles and is highly useful to form ultrasensitive MRI contrast agents for liver imaging [63] These high-yield designs, along with suitable detoxification pathways of nanoparticles, hold immense implications for safe utility in the human body Q-dots The health hazards posed by Q-dots depend on their size, concentration [64], type of... cytotoxicity under 1000 µg/ml [51] Another study conducted recently, involving lipophilically coated silica nanoparticles and alumina nanoparticles in the hexagonal closepacked a structure, found that the nanoparticles have potential to fight Grasserie, a lethal polyorganotrophic disease caused by Bombyx mori nucleopolyhedrovirus, the fifth instar silkworm larvae The nanoparticles cause morphological transformation... potential of nanometals will reach a new height if they can work synergistically | Review with biomolecules to be self-guided automatic machines, having enough force to precisely reconstruct the molecular structure of damaged Executive summary Background The medicinal industry has seen an amazing growth in nanoscale science over the last four decades; to the extent that products containing metallic nanoparticles... oxide nanoparticles are excellent hyperthermia and MRI contrast agents due to their high magnetic moment, which leads to local magnetic field inhomogeneity Iron oxide nanoparticles are effective tools for separating proteins and detection of DNA/RNA molecules with a single-base difference Q-dots Q-dots are 2–10 nm sized chalcogenides of cadmium or zinc They constitute the metallic core of semiconductors,... oxidative sites and also prevents direct contact between nanoparticles and cells Tetramethylammonium 11-aminoundecanoate-coated iron nanoparticles are found to be nontoxic at 0.110 mg/ml and cytotoxic at 100 mg/ml [60] For clinical utility, efforts should be made to improve magnetic properties of iron oxide nanoparticles, and thereby increase relaxivities by controlling the composition, oxidation state, . ‘‘silver nanomaterials’’ refers to any silver-containing materials with enhanced activity due to their nanoscale features. In some cases, commercial products containing metallic silver nanoparticles. (Auerbach 2003) J Nanopart Res (2010) 12:1531–1551 1535 123 Commercially available silver nanopowders at a concentration of 300 lg/mL and SMAD-produced silver nanoparticles at a concentration of. effects of silver nanoparticles. Nanomed Nanotechnol 3:95–101. doi:10.1016/j .nano. 2006.12.001 Kim K, Sung W, Moon S, Choi J, Kim J, Lee D (2008a) Antifungal effect of silver nanoparticles on dermato- phytes.

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