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articles Jain et al. alterations in various antioxidant enzyme systems. Further, ROS production has been found in nanoparticles as diverse as C60 fullerenes,40 single-walled carbon nanotubes,41 quantum dots,42 and ultrafine particles.43 Studies on rat liver derived cell line (BRL 3A) showed that there was a significant increase in ROS and decrease in GSH levels at 25 and 50 μg/mL of Ag (15, 100 nm).30 A significant elevation of lipid peroxidation and marginal GSH depletion was demonstrated in a fish model upon exposure to fullerenes.40 Therefore levels of antioxidant enzymes, viz., catalase, superoxide dismutase, glutathione reduced content, glutathione peroxidase and lipid peroxidation, were moni- tored after exposing the cells to ∼(1/2)IC50 (125 μg/mL) SNP in the present study. The results obtained, i.e., enhancement of GSH (∼1.1-fold), catalase (∼1.1-fold) and SOD (∼1.4- fold), indicated that Hep G2 cells were protected from oxidative stress. Thus, oxidative stress due to SNP does not persist long enough to cause oxidative damage to Hep G2 cells. It is now well established that the generation or external addition of ROS can cause cell death by two distinct cell death pathways, viz., apoptosis or necrosis. Necrosis is detrimental for wound healing and often results in healing with scar formation.44 ROS are known to activate caspases, which are considered as the executioners of apoptosis.45,46 Involvement of caspases in silver nanoparticles mediated apoptosis in the baby hamster kidney (BHK21) and human colon adenocarcinoma (HT29) cell lines has also been (39) Li, N.; Sioutas, C.; Cho, A.; Schmitz, D.; Misra, C.; Sempf, J. Ultrafine particulate pollutants induce oxidative stress and mito- chondrial damage. EnViron. Health Perspect. 2003, 111, 455– 460. (40) Oberdorster, G.; Sharp, Z.; Atudorei, V.; Elder, A.; Gelein, R.; Kreyling, W.; Cox, C. Translocation of inhaled ultrafine particles to the brain. Inhalation Toxicol. 2004, 16, 437–445. (41) Shvedova, A. A.; Kisin, E.; Keshava, N.; Murray, A. R.; Gorelik, O.; Arepalli, S. Cytotoxic and genotoxic effects of single wall carbon nanotube exposure on human Keratinocytes and bronchial epithelial cells [Abstract]. In Abstracts of Papers, 227th National Meeting of the American Chemical Society, Anaheim, CA, 27 March-1 April 2004; American Chemical Society: Washington, DC, 2004; IEC 20. (42) Derfus, A. M.; Chan, W. C. W.; Bhatia, S. N. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett. 2004, 4, 11–18. (43) Brown, D. M.; Wilson, M. R.; MacNee, W.; Stone, V.; Donaldson, K. Size-dependent proinflammatory effects of ultrafine polystyrene particles: a role for surface area and oxidative stress in the enhanced activity of ultrafines. Toxicol. Appl. Pharmacol. 2001, 175, 191–199. (44) Tian, J.; Wong, K. K. Y.; Ho, C. M.; Lok, C. N.; Yu, W. Y.; Che, C. M.; Chiu, J. F.; Paul, K. H. T. Topical delivery of silver nanoparticles promotes wound healing. ChemMedChem 2007, 2, 129–136. (45) Cohen, G. M. Caspases: the executioners of apoptosis. Biochem. J. 1997, 326, 1–16. (46) Fadeel, B.; Ahlin, A.; Henter, J. I.; Orrenius, S.; Hampton, M. B. Involvement of caspases in neutrophil apoptosis: regulation by reactive oxygen species. Blood 1998, 92, 4808–4818. shown.47 The correlation between oxidative stress and apoptosis, as explained above, prompted us to investigate the type of cell death in SNP toxicity. The type of cell death after SNP exposure was evaluated by caspase-3 activity assays, fluorescence microscopy and CLSM studies. Caspase-3 activity assay data clearly show that, at concentrations up to 250 μg/mL, cell death occurs mainly due to apoptosis. Cytotoxicity (necrosis) at higher doses of SNP (>250 μg/mL) could be clearly demonstrated by total lack of caspase-3 activity. Fluorescence light microscopy with differential uptake of fluorescent DNA binding dyes (AO/EB staining) is a method of choice (for its simplicity, rapidity, and accuracy) that distinguishes between apoptotic and necrotic cell populations. Acridine orange (AO) permeates all cells and makes the nuclei appears green. Ethidium bromide (EB) is only taken up by cells when cytoplasmic membrane integrity is lost, and stains the nucleus red. EB also dominates over AO. Thus live cells have a normal green nucleus; early apoptotic cells have bright green nucleus with condensed or fragmented chromatin; late apoptotic cells display condensed and fragmented orange chromatin; cells that have died from direct necrosis have a structurally normal orange nucleus.48 To support these findings, typical apoptotic or necrotic features in cells were also observed under CLSM. Apoptotic cell population is higher at ∼(1/2)IC50 SNP and necrotic cell population is several fold (∼7-fold) higher at ∼2 × IC50 SNP. Apoptotic cell death would not lead to undesirable side reactions that are predominant during necrosis. Similar studies were done on the baby hamster kidney (BHK21) and human colon adenocarcinoma (HT29) cell lines where necrotic cell death was observed at silver nanoparticle concentrations >44.0 μg/ mL.47 Results obtained in the present study indicate safety of SNP even at ∼(1/2)IC50 SNP (251 μg/mL) concentration in liver derived cells. The data on PAE indicated that dose regimen of the SNP formulation should ensure sustained release of the drug, and hence a formulation (S-gel) containing SNP for topical application was developed. At higher concentration of silver (0.1 mg/g) in S-gel, a significantly wider zone of inhibition was observed than that with the S-gel containing less silver, indicating a dose-dependent activity. When a standard commercial preparation, 1% silver sulfadiazine (SSD), was tested against P. aeruginosa, the inhibition zone was 23 mm, which was similar to S-gel (0.1 mg/g), indicating that S-gel formulation showed antibacterial activity, comparable to silver sulfadiazine albeit at 30-fold less silver concentration. The wound healing properties of silver nanoparticles in an animal model and rapid healing and better cosmetic appearance in a dose-dependent manner were observed by (47) Gopinath, P.; Gogoi, S. K.; Chattopadhyay, A.; Ghosh, S. S. Implications of silver nanoparticle induced cell apoptosis for in vitro gene therapy. Nanotechnology 2008, 19, 1–10. (48) Renvoize, C.; Biola, A.; Pallardy, M.; Breard, J. Apoptosis: Identification of dying cells. Cell Biol. Toxicol. 1998, 14, 111– 120. 1400 MOLECULAR PHARMACEUTICS VOL. 6, NO. 5PDF Image | Silver Nanoparticles in Therapeutics: Antimicrobial Gel
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