Synthesis of S-nitrosoglutathione-alginate for prolonged delivery of nitric oxide in intestines

Abstract

S-nitrosothiols are a class of NO-donors currently under investigation for the treatment of various diseases. In this study, we developed a novel NO-donor (S-nitrosoglutathione-alginate, SNA) by cross-linking alginate with S-nitrosothiols, which can deliver NO in a sustained manner. This compound can be further evaluated for oral delivery to treat Crohn's disease. This new compound was prepared using a two-step procedure involving (I) linkage of reduced glutathione to alginate and (II) post-nitrosation with sodium nitrite (NaNO 2 ). The amount of linked thiol moieties for the possible nitrosation was calculated using Ellman's method, and the amount of NO abducted on the polymer was calculated using the Griess-Saville method. An ex vivo model (i.e. Ussing chamber) was used to investigate the permeation of this new NO-donor across the rat intestinal barrier. We obtained polymers with different numbers of abducted NOs (174 ± 21 mmol/g for SNA F1 and 468 ± 23 mmol/g for SNA F2) depending on the procedure used for nitrosation. In the ex vivo studies in the Ussing chamber, SNA F2 exhibited a sustained release for at least 10 h. The effect of pH on the stability of the new compound was also investigated, and the new compound was more stable at a mildly basic pH of 8.4 where 73% remained after 1 week. However, only 50% remained after 1 week at an acidic pH of 1.2. In the cytotoxicity studies (Caco2), this compound was nontoxic at concentrations of less than 200 mM.

Glutathionylation: a regulatory role of glutathione in physiological processes

“…In in vivo experiments, LPS-challenged rats showed a drop in serum NO, and significant rise in creatinine and BUN, which were successfully countered with GSNO treatment (179). The therapeutic potential of GSNO is yet to be established with the application of new GSNO nanocarriers (180,181) or administration methods suitable for oral applications as target drugs (182).…”

In vivo pharmacological activity and biodistribution of S-nitrosophytochelatins after intravenous and intranasal administration in mice

“…Two compounds were synthesized with NO loading 174 ± 21 μmol/g and 468 ± 23 μmol/g respectively. An ex vivo permeation study showed that these compounds can exhibit a sustained release for at least 10 h [44] Encapsulation of RSNO in polymeric nanoparticles also provides a promising strategy in sustaining NO release from RSNO. Eudragit ® RL was used to prepare GSNO-loaded nanoparticles (GSNO-NP).…”

The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

“…GSNO has been shown to promote the S -nitrosation of catalase, which modulates its activity in processes like growth, development and response to stress in plants ( Corpas et al, 2019 ) and animals ( Tyther et al, 2007 ), and GSNO-directed inhibition of catalase by S -nitrosation has been linked to obesity in humans ( Palma et al, 2020 ). Moreover, S -nitrosothiols such as GSNO have been used for many years as cardiovascular therapeutics and are currently under investigation as treatments for other diseases, including Crohn’s disease ( Shah et al, 2016 ). There, the ability of GSNO to regulate and modulate the actions of signaling cascades by post-translational modifications like S -nitrosation could account for its efficacy as a therapeutic for a variety of conditions.…”