Drug Delivery Letters   Send Orders for Reprints to reprints@benthamscience.ae Drug Delivery Letters, 2016, 6, 3-10 3 REVIEW ARTICLE Recent Trends on the Use of Nanoparticles for Nitric Oxide Delivery in Antimicrobial Applications 2210-304X/16 $58.00+.00 © 2016 Bentham Science Publishers Sayeed Hasan 1 , Nicky Thomas 1 , Benjamin Thierry 2 , Sarah Vreugde 3 , Peter-John Wormald 3 and Clive A. Prestidge 1* 1 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia; 2 Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia; c Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia Received: December 15, 2015 Revised: February 09, 2016 Accepted: April 22, 2016 DOI: 10.2174/22103031066661605061618 20 Abstract: Nitric oxide (NO) has a multitude of biological activities and has great potential for numerous therapeutic applications. However, its small size, short half- life and instability under physiological conditions make achieving therapeutic levels challenging. Nanoparticle carriers offer potential to overcome the various physio- chemical and biological challenges for effective NO delivery. State of the art in the development and application of nanoparticle based carrier sys- tems for the encapsulation and delivery of NO and NO-precursor molecules are criti- cally reviewed. Specific focus is directed to the antimicrobial performance of NO delivered by polymeric, inorganic and lipid based- nanocarriers. NO-precursor molecules have been identified as effective approaches for NO deliv- ery. Liposomes, silica particles, hydrogels and polymeric nanoparticles offer specific properties and per- formance to overcome the NO delivery challenges and have demonstrated enhanced therapeutic efficacy; some mechanistic insight is given. Specific antimicrobial and infected wound healing applications of NO-nanocarriers are highlighted and these show significant promise for translation to clinical applica- tion. Polymeric, inorganic and lipid based- nanocarriers are effective encapsulation and delivery systems for NO-precursors. Prospects for NO delivery in the treatment of infectious diseases and wound care man- agement are evident. Keywords: Anti-microbial, nanocarriers, nanotechnology, nitric oxide donor, nitric oxide, polymer. 1. INTRODUCTION Until the late 1980’s the chemical nature of the endothel- ium derived relaxing factor (EDRF) remained elusive despite numerous efforts by research groups to unravel its structure. This changed in 1987 when Furchatt, Ignarro and Murad discovered that the gas nitric oxide (NO) was identical with EDRF. Since then medical and scientific interest in NO has dramatically increased. The importance of the discovery of NO was further demonstrated by the proclamation of nitric oxide as “molecule of the year” by Science in 1992 and the award of the Nobel Prize in Medicine to the three pioneering researchers in 1998 [1]. Nitric oxide (NO) is a free-radical gas that is unstable in an oxygen-containing environment. Nitric oxide is a small molecule associated with a wide range of physiological *Address correspondence to this author at the School of Pharmacy and Medical Sciences; Division of Health Sciences, University of South Austra- lia, Adelaide, South Australia 5001; Tel: +61 8 83023569; Fax: +61 8 83023683; E-mail: clive.prestidge@unisa.edu.au processes in the cardiovascular, immune and nervous system as well as in skin physiology [2-4]. In addition to its benefi- cial effects, the toxicity of NO leads to antioxidant defi- ciency [5, 6]. Recent research has focused on NO as a major target of the microbial pathogens because of its inherent antimicrobial properties [5]. The antimicrobial effect of en- dogenous NO changes with varying concentrations. At low concentrations, NO acts as a potent nitrosating agent to pro- mote signalling and cellular damage [7] in the presence of superoxide, forming highly cytotoxic peroxynitrite. In con- trast, at high concentrations NO generates nitrosating species which alter DNA replication, regulate protein and cell func- tion, thus inhibit or kill target pathogens [8]. Additionally, NO also functions as a mediator in each phase of the wound healing cascade, i.e. keratinocyte maturation, angiogenesis and matrix deposition. Consequently, the fact that NO medi- ated therapies are greatly promoting proper wound healing is becoming apparent. Gaseous nitric oxide is rarely used in pharmaceutical research as an antimicrobial agent against infectious diseases A R T I C L E H I S T O R Y