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WIREs Nanomed Nanobiotechnol

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Use of nitric oxide nanoparticulate platform for the treatment of skin and soft tissue infections

Advanced Review

Adam J. Friedman, Allison J. Kutner

Published Online: May 09 2013

DOI: 10.1002/wnan.1230

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The incidence of skin and soft tissue infections (SSTI) due to multi‐drug resistant pathogens is increasing. The concomitant increase in antibiotic use along with the ease with which organisms develop mechanisms of resistance have together become a medical crisis, underscoring the importance of developing innovative and effective antimicrobial strategies. Nitric oxide (NO) is an endogenously produced molecule with many physiologic functions, including broad spectrum antimicrobial activity and immunomodulatory properties. The risk of resistance to NO is minimized because NO has multiple mechanisms of antimicrobial action. NO's clinical utility has been limited largely because it is highly reactive and lacks appropriate vehicles for storage and delivery. To harness NO's antimicrobial potential, a variety exogenous NO delivery platforms have been developed and evaluated, yet limitations preclude their use in the clinical setting. Nanotechnology represents a paradigm through which these limitations can be overcome, allowing for the encapsulation, controlled release, and focused delivery of NO for the treatment of SSTI. WIREs Nanomed Nanobiotechnol 2013. doi: 10.1002/wnan.1230 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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Synthesis of nitric oxide (NO). Endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) calcium‐dependent, calmodulin‐regulated enzymes. They are constitutively expressed and catalyze the conversion of arginine to citrulline. Inducible NOS (iNOS) converts arginine to citrulline in a calcium‐independent fashion, and is activated by bacterial endotoxins and proinflammatory cytokines. (Reprinted with permission from Ref . Copyright 1998 Nature Publishing Group)

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Nitric oxide‐releasing nanoparticles (NO)‐nps decrease methicillin‐resistant Staphylococcus aureus (MRSA)‐infected intramuscular abscess area. Induced MRSA‐infected intramuscular abscesses were clinically evaluated on day 4 after infection. These images, untreated (a), treated with vancomycin (b), treated topically with NO‐nps (c), or treated intralesionally with NO‐nps (d) are representative of the clinical appearance of these lesions Arrows denote abscesses. (Reprinted with permission from Ref . Copyright 2012 Landes Bioscience)

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Nitric oxide‐releasing nanoparticles (NO‐nps) decrease methicillin‐resistant Staphylococcus aureus (MRSA)‐infected intradermal abscess area. Abscesses were untreated, treated with nanoparticles without NO (np), or treated with NO‐np, day 4. Arrows denote abscesses; inset demonstrates a representative purulent abscess 4 days after MRSA infection. Bar = 5 mm. (Reprinted with permission from Ref . Copyright 2009 Public Library of Science)

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Nitric oxide‐releasing nanoparticles (NO‐nps) accelerated healing in Candida albicans‐infected burn wounds. Wounds were untreated, treated with nanoparticles without NO (np), or treated with NO‐np. Bar = 5 mm. (Reprinted with permission from Ref . Copyright 2012 Frontiers)

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Nitric oxide‐releasing nanoparticles (NO‐nps) accelerated healing in Acinetobacter baumannii‐infected excisional wounds. Wounds were untreated, treated with nanoparticles without NO (np), or treated with NO‐np, 3 days post‐infection. (Reprinted with permission from Ref . Copyright 2010 Landes Bioscience)

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Nitric oxide‐releasing nanoparticles (NO‐nps) accelerated healing in methicillin‐resistant Staphylococcus aureus (MRSA)‐infected excisional wounds. Wounds were untreated, treated with nanoparticles without NO (np), or treated with NO‐np. (Reprinted with permission from Ref . Copyright 2009 Nature Publishing Group)

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(a) S‐nitrosoglutathione (GSNO) structure and (b) S‐nitroso‐N‐acetylcysteine (SNAC) structure. (Reprinted with permission from Ref . Copyright 2004 Wiley‐Blackwell)

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References

Friedman, A, Blecher, K, Sanchez, D, Tuckman‐Vernon, C, Gialanella, P, Friedman, J, Martinez, L, Nosanchuk, J. Susceptibility of Gram‐positive and ‐negative bacteria to novel nitric oxide‐releasing nanoparticle technology. Virulence 2011, 2:217–221.
Marra, F, Patrick, D, Chong, M, McKay, R, Hoang, L, Bowie, W. Population‐based study of the increased incidence of skin and soft tissue infections and associated antimicrobial use. Antimicrob Agents Chemother 2012, 56:6243–6249.
Huttner, B, Goossens, H, Verheij, T, Harbarth, S, on behalf of the CHAMP consortium. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high‐income countries. Lancet Infect Dis 2010, 10:17–31.
Englander, L, Friedman, A. Nitric oxide nanoparticle technology: a novel antimicrobial agent in the context of current treatment of skin and soft tissue infection. J Clin Aesthet Dermatol 2010, 3:45–50.
Lautz, T, Raval, M, Barsness, K. Increasing national burden of hospitalizations for skin and soft tissue infections in children. J Pediatr Surg 2011, 46:1935–1941.
Frei, C, Makos, B, Daniels, K, Oramasionwu, C. Emergence of community‐acquired methicillin‐resistant Staphylococcus aureus skin and soft tissue infections as a common cause of hospitalization in United States children. J Pediatr Surg 2010, 45:1967–1974.
Miller, C, McMullin, B, Ghaffari, A, Miller, J, Stenzler, A, Pick, N, Roscoe, D, Ghahary, A, Road, J, Av Gay, Y. Gaseous nitric oxide bactericidal activity retained during intermittent high‐dose short duration exposure. Nitric Oxide 2009, 20:16–23.
Privett, B, Broadnax, A, Bauman, S, Riccio, D, Schoenfisch, MH. Examination of bacterial resistance to exogenous nitric oxide. Nitric Oxide 2012, 26:169–173.
Del Rosso, J. Wound care in the dermatology office: where are we in 2011? J Am Acad Dermatol 2011, 64:S1–S7.
Hetrick, EM, Shin, JH, Stasko, NA, Johnson, CB, Wespe, DA, Holmuhamedov, E, Schoenfisch, MH. Bactericidal efficacy of nitric oxide‐releasing silica nanoparticles. ACS Nano 2008, 2:235–246.
McElhaney‐Feser, G, Raulli, R, Cihlar, R. Synergy of nitric oxide and azoles against Candida species in vitro. Antimicrob Agents Chemother 1998, 42:2342–2346.
Carpenter, A, Slomberg, D, Rao, K, Schoenfisch, M. Influence of scaffold size on bactericidal activity of nitric oxide‐releasing silica nanoparticles. ACS Nano 2011, 5:7235–7244.
Fang, FC. Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide‐related antimicrobial activity. J Clin Invest 1997, 99:2818–2825.
Green, S, Nacy, C. Antimicrobial and immunopathologic effects of cytokine‐induced nitric oxide synthesis. Curr Opin Infect Dis 1993, 6:384–396.
Schairer, D, Chouake, J, Nosanchuk, J, Friedman, A. The potential of nitric oxide releasing therapies as antimicrobial agents. Virulence 2012, 3:271–279.
Friedman, A, Han, G, Navati, M, Chacko, M, Gunther, L, Alfieri, A, Friedman, J. Sustained release nitric oxide releasing nanoparticles: characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites. Nitric Oxide 2008, 19:12–20.
Cabrales, P. Nanoengineering bactericidal nitric oxide therapies. Virulence 2011, 2:185–187.
Weller, R. Nitric oxide‐containing nanoparticles as an antimicrobial agent and enhancer of wound healing. J Invest Dermatol 2009, 129:2335–2337.
Shin, J, Metzger, S, Schoenfisch, M. Synthesis of nitric oxide‐releasing silica nanoparticles. J Am Chem Soc 2007, 129:4612–4619.
Pacelli, R, Wink, D, Cook, JK, Krishna, MC, DeGraff, W, Friedman, N, Tsokos, M, Samuni, A, Mitchell, J. Nitric oxide potentiates hydrogen peroxide‐induced killing of Escherichia coli. J Exp Med 1995, 182:1469–1479.
Ormerod, A, Copeland, P, Hay, I, Husain, A, Ewen, S. The inflammatory and cytotoxic effects of a nitric oxide releasing cream on normal skin. J Invest Dermatol 1999, 113:392–397.
Medeiros, R, Figueiredo, C, Passos, G, Calixto, J. Reduced skin inflammatory response in mice lacking inducible nitric oxide synthase. Biochem Pharmacol 2009, 78:390–395.
Friedman, A, Friedman, J. New biomaterials for the sustained release of nitric oxide: past, present and future. Expert Opin Drug Deliv 2009, 6:1113–1122.
Bruch‐Gerharz, D, Ruzicka, T, Kolb‐Bachofen, V. Nitric oxide in human skin: current status and future prospects. J Invest Dermatol 1998, 110:1–7.
Jones, ML, Ganopolsky, JG, Labbe, A, Prakash, S. A novel nitric oxide producing probiotic patch and its antimicrobial efficacy: preparation and in vitro analysis. Appl Microbiol Biotechnol 2010, 87:509–516.
Ghaffari, A, Neil, D, Ardakani, A, Road, J, Ghahary, A, Miller, C. A direct nitric oxide gas delivery system for bacterial and mammalian cell cultures. Nitric Oxide 2005, 12:129–140.
Nacharaju, P, Tuckman‐Vernon, C, Maier, KE, Chouake, J, Friedman, A, Cabrales, P, Friedman, JM. A nanoparticle delivery vehicle for S‐nitroso‐N‐acetyl cysteine: sustained vascular response. Nitric Oxide 2012, 27:150–160.
Cariello, A, Bispo, P, de Souza, G, Pignatari, A, de Oliveira, M, Hofling‐Lima, A. Bactericidal effect of S‐nitrosothiols against clinical isolates from keratitis. Clin Ophthalmol 2012, 6:1907–1914.
De Groote, MA, Fang, FC. NO inhibitions: antimicrobial properties of nitric oxide. Clin Infect Dis 1995, 21(suppl 2):S162–S165.
Weller, R, Price, R, Ormerod, A, Benjamin, N, Leifert, C. Antimicrobial effect of acidified nitrite on dermatophyte fungi, Candida and bacterial skin pathogens. J Appl Microbiol 2001, 90:648–652.
Sanchez, D, Nosanchuk, J, Friedman, A. The purview of nitric oxide nanoparticle therapy in infection and wound healing. Nanomedicine 2012, 7:933–936.
Flatley, J, Barrett, J, Pullman, S, Hughes, M, Green, J, Poole, R. Transcriptional responses of Escherichia coli to S‐nitrosoglutathione under defined chemostat conditions reveal major changes in methionine biosynthesis. J Biol Chem 2005, 280:10065–10072.
Schairer, D, Martinez, L, Blecher, K, Chouake, J, Nacharaju, P, Gialanella, P, Friedman, J, Nosanchuk, J, Friedman, A. Nitric oxide nanoparticles: pre‐clinical utility as a therapeutic for intramuscular abscesses. Virulence 2012, 3:62–67.
Friedman, AJ, Blecher, K, Schairer, D, Tuckman‐Vernon, C, Nacharaju, P, Sanchez, D, Gialanella, P, Martinez, LR, Friedman, JM, Nosanchuk, JD. Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S‐nitrosoglutathione. Nitric Oxide 2011, 25:381–386.
Bogdan, C. Nitric oxide and the immune response. Nat Immunol 2001, 2:907–916.
MacLean, A, Wei, X, Huang, F, Al‐Alem, U, Chan, W, Liew, F. Mice lacking inducible nitric‐oxide synthase are more susceptible to herpes simplex virus infection despite enhanced Th1 cell responses. J Gen Virol 1998, 79:825–830.
Fagundes, C, Costa, V, Cisalpino, D, Amaral, FS, Souza, PR, Souza, RS, Ryffel, B, Vieira, L, Silva, T, Atrasheuskaya, A, et al. IFN‐γ production depends on IL‐12 and IL‐18 combined action and mediates host resistance to dengue virus infection in a nitric oxide‐dependent manner. PLoS One Trop Dis 2011, 5:1449.
Zhou, X, Potoka, D, Boyle, P, Nadler, E, McGinnis, K, Ford, H. Aminoguanidine renders inducible nitric oxide synthase knockout mice more susceptible to Salmonella typhimurium infection. FEMS Microbiol Lett 2002, 206:93–97.
MacFarlane, A, Schwacha, M, Eisenstein, T. In vivo blockage of nitric oxide with aminoguanidine inhibits immunosuppression induced by an attenuated strain of Salmonella typhimurium, potentiates Salmonella infection, and inhibits macrophage and polymorphonuclear leukocyte influx into the spleen. Infect Immun 1999, 67:891–898.
Ghaffari, A, Miller, CC, McMullin, B, Ghahary, A. Potential application of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxide 2006, 14:21–29.
Major, T, Panmanee, W, Mortensen, J, Gray, L, Hoglen, N, Hassett, D. Sodium nitrite‐mediated killing of the major cystic fibrosis pathogens Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia under anaerobic planktonic and biofilm conditions. Antimicrob Agents Chemother 2010, 54:4671–4677.
Chen, C, Shi, Y, Song, J, Qi, Q, Gu, L, Wang, P. Delivery of nitric oxide released from β‐Gal‐NONOate activation by β‐galactosidase and its activity against Escherichia coli. Biol Pharm Bull 2006, 29:1239–1241.
MacMicking, J, Nathan, C, Hom, G, Chartrain, N, Fletcher, D, Trumbauer, M, Stevens, K, Xie, Q, Sokol, K, Hutchinson, N, et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995, 81:641–650.
Kawanishi, M. Nitric oxide inhibits Epstein‐Barr virus DNA replication and activation of latent EBV. Intervirology 1995, 38:206–213.
Akerstrom, S, Mousavi‐Jazi, M, Klingstrom, J, Leijon, M, Lundkvist, A, Mirazimi, A. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol 2005, 79:1966–1969.
Wei, Z, Wang, X, Ning, X, Wang, Y, Zhang, H, Wang, D, Chen, H, Cui, B. Nitric oxide inhibits the replication cycle of porcine parvovirus in vitro. Arch Virol 2009, 154:999–1003.
Ormerod, A, White, MI, Shah, SAA, Benjamin, N. Molluscum contagiosum effectively treated with a topical acidified nitrite, nitric oxide liberating cream. Br J Dermatol 1999, 141:1051–1053.
de Souza, G, Yokoyama‐Yasunaka, J, Seabra, A, Miguel, D, De Oliveira, M, Uliana, S. Leishmanicidal activity of primary S‐nitrosothiols against Leishmania major and Leishmania amazonensis: implications for the treatment of cutaneous leishmaniasis. Nitric Oxide 2006, 15:209–216.
Zeina, B, Banfield, C, al‐Assad, S. Topical glyceryl trinitrate: a possible treatment for cutaneous leishmaniasis. Clin Exp Dermatol 1997, 22:244–245.
Augusto, O, Linares, E, Giorgio, S. Possible roles of nitric oxide and peroxynitrite in murine leishmaniasis. Braz J Med Biol Res 1996, 29:853–862.
Vespa, G, Cunha, F, Silva, J. Nitric oxide is involved in control of Trypanosoma cruzi‐induced parasitemia and directly kills the parasite in vitro. Infect Immun 1994, 62:5177–5182.
Rockett, K, Awburn, M, Cowden, W, Clark, I. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun 1991, 59:3280–3283.
Tohyama, M, Kawakami, K, Futenma, M, Saito, A. Enhancing effect of oxygen radical scavengers on murine macrophage anticryptococcal activity through production of nitric oxide. Clin Exp Immunol 1996, 103:436–441.
Alspaugh, J, Granger, D. Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage‐mediated cytostasis. Infect Immun 1991, 59:2291–2296.
Granger, D, Hibbs, JJ, Perfect, J, Durack, D. Metabolic fate of l‐arginine in relation to microbiostatic capability of murine macrophages. J Clin Invest 1990, 85:264–273.
Ghaffari, A, Jalili, R, Ghaffari, M, Miller, C, Ghahary, A. Efficacy of gaseous nitric oxide in the treatment of skin and soft tissue infections. Wound Repair Regen 2007, 15:368–377.
Weller, R, Ormerod, A, Hobson, R, Benjamin, N. A randomized trial of acidified nitrite cream in the treatment of tinea pedis. J Am Acad Dermatol 1998, 38:559–563.
Jowkar, F, Jamshidzadeh, A, Pakniyat, S, Namazi, M. Efficacy of nitric‐oxide liberating cream on pityriasis versicolor. J Dermatolog Treat 2010, 21:93–96.
Ormerod, A, Shah, A, Li, H, Benjamin, N, Ferguson, G, Leifert, C. An observational prospective study of topical acidified nitrite for killing methicillin‐resistant Staphylococcus aureus (MRSA) in contaminated wounds. BMC Res Notes 2011, 4:458.
Seabra, A, Fitzpatrick, A, Paul, J, De Oliveira, M, Weller, R. Topically applied S‐nitrosothiol‐containing hydrogels as experimental and pharmacological nitric oxide donors in human skin. Br J Dermatol 2004, 151:977–983.
Davies, K, Wink, D, Saavedra, J, Keefer, L. Chemistry of the diazeniumdiolates. 2. Kinetics and mechanism of dissociation to nitric oxide in aqueous solution. J Am Chem Soc 2001, 123:5473–5481.
Keefer, L. Nitric oxide (NO)‐ and nitroxyl (HNO)‐generating diazeniumdiolates (NONOates): emerging commercial opportunities. Curr Top Med Chem 2005, 5:625–636.
Keefer, L. Progress toward clinical application of the nitric oxide‐releasing diazeniumdiolates. Annu Rev Pharmacol Toxicol 2003, 43:585–607.
Jones, M, Ganopolsky, J, Labbe, A, Gilardino, M, Wahl, C, Martoni, C, Prakash, S. Novel nitric oxide producing probiotic wound healing patch: preparation and in vivo analysis in a New Zealand white rabbit model of ischaemic and infected wounds. Int Wound J 2012, 9:330–343.
Fox, S, Wilkinson, T, Wheatley, P, Xiao, B, Morris, R, Sutherland, A, Simpson, A, Barlow, PG, Butler, A, Megson, I, et al. NO‐loaded Zn(2+)‐exchanged zeolite materials: a potential bifunctional anti‐bacterial strategy. Acta Biomater 2010, 6:1515–1521.
Blecher, K, Nasir, A, Friedman, A. The growing role of nanotechnology in combating infectious disease. Virulence 2011, 2:395–401.
Han, G, Tar, M, Kuppam, D, Friedman, A, Melman, A, Friedman, J, Davies, K. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction. J Sex Med 2010, 7:224–233.
Han, G, Martinez, LR, Mihu, MR, Friedman, AJ, Friedman, JM, Nosanchuk, JD. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in a murine model of infection. PLoS One 2009, 4:e7804.
Martinez, L, Han, G, Chacko, M, Mihu, M, Jacobson, M, Gialanella, P, Friedman, A, Nosanchuk, J, Friedman, J. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infection. J Invest Dermatol 2009, 129:2463–2469.
Mihu, MR, Sandkovsky, U, Han, G, Friedman, JM, Nosanchuk, JD, Martinez, LR. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence 2010, 1:62–67.
Macherla, C, Sanchez, DA, Ahmadi, MS, Vellozzi, EM, Friedman, AJ, Nosanchuk, JD, Martinez, LR. Nitric oxide releasing nanoparticles for treatment of Candida albicans burn infections. Front Microbiol 2012, 3:193.
Hetrick, EM, Shin, JH, Paul, HS, Schoenfisch, MH. Anti‐biofilm efficacy of nitric oxide‐releasing silica nanoparticles. Biomaterials 2009, 30:2782–2789.
Chouake, J, Schairer, D, Kutner, A, Sanchez, D, Makdisi, J, Blecher‐Paz, K, Nacharaju, P, Tuckman‐Vernon, C, Gialanella, P, Friedman, J, et al. Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa‐infected wounds. J Drugs Dermatol 2012, 2:1471–1477.

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