Original ArticleS-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology
Graphical Abstract
Previously, we demonstrated increased antimicrobial activity against E. coli with nitric oxide releasing nanoparticles (NO-np) + GSH, versus NO-np alone, due to formation of S-nitrosoglutathione (GSNO), a potent transnitrosylating agent. However, a suspension of NO-np + GSH would not be practical. In the current study, we incorporated captopril into a novel nanoparticle which can generate NO as well as S-nitrosocaptopril (SNO-CAP). In addition to sustained release of NO, SNO-CAP-np demonstrated sustained GSNO production in the presence of GSH and killed both E. coli and MRSA in a dose-dependent fashion, with a pronounced effect against E. coli.
Section snippets
Synthesis of SNO-CAP nanoparticles
A modified tetramethylorthosilicate (TMOS)-based sol–gel method was used to prepare SNO-CAP-np as previously described.17 Briefly, TMOS (3 mL) was hydrolyzed with 1 mM HCl (0.6 mL) by sonication on an ice-bath. The hydrolyzed TMOS (3 mL) was added to a buffer mixture of 1.5 mL of 0.5% chitosan, 1.5 mL of polyethylene glycol (PEG) 400, and 24 mL of 50 mM phosphate (pH 7.4) containing 0.225 M nitrite and 0.28 M captopril. The mixture was left at room temperature overnight in the dark for polymerization. A
SNO-CAP-np size characterization
SNO-CAP-np size determined by scanning electron microscopy (SEM) is congruent with previous data in which our similarly designed NO-np was measured via transmission electron microscopy (TEM).17 While previous TEM preparations were imaged to show individual nanoparticles of 10 nm in diameter,17 our current SEM preparations yielded nanoaggregates of 60-80 nm in diameter (measured from 100 nanoaggregates). However, individual nanoparticles could be visualized within many of the nanoaggregates which
Discussion
Due to the continued threat of antibiotic resistance, it is necessary to pursue technologies that employ innovative, multi-mechanistic methods to kill bacteria and limit the chance for adverse events associated with their use. In the current study, SNO-CAP-np demonstrated sustained nitrosylation activity via production of GSNO in the presence of GSH, which was maintained at a steady concentration over an extended period of time. In addition, SNO-CAP-np released and maintained significant levels
References (29)
- et al.
Nanotechnology as a therapeutic tool to combat microbial resistance
Adv Drug Deliv Rev
(2013) - et al.
Nonspecific defence mechanism: the role of nitric oxide
Immunol Today
(1991) - et al.
Biphasic regulation of leukocyte superoxide generation by nitric oxide and peroxynitrite
J Biol Chem
(2000) - et al.
Tolerance to relaxation in rat aorta: comparison of an S-nitrosothiol with nitroglycerin
Eur J Pharmacol
(1987) Nitric oxide and thiol groups
Biochim Biophys Acta
(1999)- et al.
Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S-nitrosoglutathione
Nitric Oxide
(2011) - et al.
Sustained release nitric oxide releasing nanoparticles: characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites
Nitric Oxide
(2008) - et al.
A nanoparticle delivery vehicle for S-nitroso-N-acetyl cysteine: sustained vascular response
Nitric Oxide
(2012) - et al.
Determination of the Escherichia coli S-nitrosoglutathione response network using integrated biochemical and systems analysis
J Biol Chem
(2008) - et al.
Transcriptional responses of Escherichia coli to S-nitrosoglutathione under defined chemostat conditions reveal major changes in methionine biosynthesis
J Biol Chem
(2005)
Methicillin-resistant Staphylococcus aureus bacterial nitric-oxide synthase affects antibiotic sensitivity and skin abscess development
J Biol Chem
NO inhibitions: antimicrobial properties of nitric oxide
Clin Infect Dis
Nitric oxide and the immune response
Nat Immunol
Requirement for type 2 NO synthase for IL-12 signaling in innate immunity
Science
Cited by (12)
Roles and current applications of S-nitrosoglutathione in anti-infective biomaterials
2022, Materials Today BioCitation Excerpt :In addition, NO-np plus GSH completely inhibited P. aeruginosa within one day and accelerated healing of the infected wounds [107]. To take advantage of this finding, researchers incorporated thiol-containing captopril into NO-np to form SNO-CAP-np, which could release NO with S-nitrosocaptopril providing thiol to facilitate transnitrosylation (Fig. 5b) [108]. Upon exposure to GSH, SNO-CAP-np exhibited stronger transnitrosylation activity and increased GSNO formation compared to that of NO-np, and showed potent antimicrobial properties against E. coli and MRSA in a dose-dependent manner.
Challenging development of storable particles for oral delivery of a physiological nitric oxide donor
2020, Nitric Oxide - Biology and ChemistryCitation Excerpt :An attractive alternative strategy mimicking the physiology could be to encapsulate high molecular weight S-nitrosothiols, which will generate GSNO in situ by transnitrosation of physiological GSH. Previous studies with encapsulation of S-nitroso-N-acetylcysteine [43] and S-nitroso-captopril [44] proved the effectiveness of this transnitrosation approach to elicit vasodilation or anti-infectious effects after parenteral or local administration, respectively. However, despite the lower encapsulation and duration of drug release with our Eudragit® particles, the release rate itself, around 150 pmol.
Free radical-releasing systems for targeting biofilms
2020, Journal of Controlled ReleaseCitation Excerpt :One of the modes of action of free radicals includes mediating host defense mechanisms [82] that stimulate the natural elimination of microbes. This process involves the high production of reactive oxygen species which leads to increased sensitivity of the immune cells to oxidative stress [83]. The major mechanisms of bacterial cell death initiated by reactive nitrogen and reactive oxygen species are nitrosative and oxidative stress, respectively.
Nitric Oxide-Releasing Nanoparticles as an Antimicrobial Therapeutic
2016, Nanoscience in DermatologyRecent progress in the toxicity of nitric oxide-releasing nanomaterials
2021, Materials AdvancesRecent advances in the development of nitric oxide-releasing biomaterials and their application potentials in chronic wound healing
2021, Journal of Materials Chemistry B
Funding and Conflict of Interest: SLH acknowledges NIH grants ES017552-01A2, ES016896-01, P30 ES03850, T32 ES0007060, and AFRL FA8650-05-1-5041.
JDN acknowledges National Institutes of Health/National Institute of Allergy and Infectious Diseases grant 1RC2A1087612-01.
AJF acknowledges Dermatology Foundation Career Development Award and Janssen Biotech Research Grant.
JMF, PN, and AJF are co-inventors of the technology described; however no financial conflict currently exists.