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bioRxiv · 10.1101/2022.10.03.510719

Inclusion Complexation of S-Nitrosoglutathione for Sustained NO Release and Reduced Device Infection

Li, W.·Wang, D.·Lao, K. U.·Wang, X.
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Abstract

S-nitrosoglutathione (GSNO) is a non-toxic 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 the NO release kinetics. 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 CD > {gamma}CD > hydroxypropyl {beta}CD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37{degrees}C, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in CD 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-CD 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.

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Li, W., Wang, D., Lao, K. U., Wang, X.. 2022-10-04. Inclusion Complexation of S-Nitrosoglutathione for Sustained NO Release and Reduced Device Infection. https://doi.org/10.1101/2022.10.03.510719

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