Inclusion Complexation of S-Nitrosoglutathione for Sustained Nitric Oxide Release from Catheter Surfaces: A Strategy to Prevent and Treat Device-Associated Infections

Abstract

S-Nitrosoglutathione (GSNO) is a nontoxic nitric oxide (NO)-donating compound that occurs naturally in the human body. The use of GSNO to deliver exogenous NO for therapeutic and protective applications is limited by the high lability of dissolved GSNO in aqueous formulations. In this paper, we report a host−guest chemistry-based strategy to modulate the GSNO reactivity and NO release kinetics for the design of antiinfective catheters and hydrogels. Cyclodextrins (CDs) are host molecules that are typically used to encapsulate hydrophobic guest molecules into their hydrophobic cavities. However, we found that CDs form inclusion complexes with GSNO, an extremely hydrophilic molecule with a solubility of over 1 M at physiological pH. More interestingly, the host−guest complexation reduces the decomposition reactivity of GSNO in the order of αCD > γCD > hydroxypropyl βCD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37 °C, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in αCD undergoes a conformational change that significantly reduces the S−NO bond distance and increases its stability. The calculated S−NO bond dissociation enthalpies of free and complexed GSNO well agree with the experimentally observed GSNO decomposition kinetics. The NO release from GSNO-CD solutions, compared to GSNO solutions, has suppressed initial bursts and extended durations, enhancing the safety and efficacy of NO-based therapies and device protections. In an example application as an anti-infective lock solution for intravascular catheters, the GSNO-αCD solution exhibits potent antibacterial activities for both planktonic and biofilm bacteria, both intraluminal and extraluminal environments, both prevention and treatment of infections, and against multiple bacterial strains, including a multidrug-resistant strain. In addition to solutions, the inclusion complexation also enables the preparation of GSNO hydrogels with enhanced stability and improved antibacterial efficacy. Since methods to suppress and control the GSNO decomposition rate are rare, this supramolecular strategy provides new opportunities for the formulation and application of this natural NO donor.

Antimicrobial efficacy of a nitric oxide-releasing ampicillin conjugate catheter lock solution on clinically-isolated antibiotic-resistant bacteria

“…The NO release levels obtained in these SNAPicillin studies were found to be lower compared to previously reported studies comprising of the less bulky and hydrophilic SNACET, GSNO, and GSNO-cyclodextrin-based NO-releasing lock solutions. 14,15,31 However, the high NO release levels seen from these previously reported studies can be attributed to the higher concentrations of solutions utilized (as high as 100 mM) compared to 10 mM concentration of SNAPicillin used in this study. Although the NO release levels from the SNAPicillin solution were observed to be lower, the antibacterial efficiency of SNAPicillin is noted to be the most efficient with 4.28 and 8.24 log reductions in S. marcescens and E. coli bacteria due to the synergy with the covalently bound ampicillin, respectively, when compared to previously reported NO-releasing lock solutions.…”

Effect of a glutathione-containing dinitrosyl iron complex on the oxidative metabolic state and crystallogenic properties of rat blood plasma: a preclinical experimental study

“…[1][2][3][4]. При этом важно отметить крайне малое время жизни молекулы монооксида азота, составляющее в среднем 6 секунд в свободном состоянии [5,6], что предъявляет высокие требования к регуляции метаболизма данного соединения и обеспечивает необходимость присутствия в организме веществ, временно депонирующих NO либо создающих условия для его синтеза в случае необходимости [7,8].…”