title: 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 (NaNO2). 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 μmol/g for SNA F1 and 468 ± 23 μmol/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 μM.
authors.affiliation: a EA 3452/CITHEFOR, Université De Lorraine , Nancy , France and.|b Department of Pharmaceutics , Faculty of Pharmacy, Gomal University , Dera Ismail Khan (KPK) , Pakistan.
authors.forename: Shefaat Ullah
authors.initials: SU
authors.lastname: Shah
authors.affiliation: a EA 3452/CITHEFOR, Université De Lorraine , Nancy , France and.
authors.forename: Marie
authors.initials: M
authors.lastname: Socha
authors.affiliation: a EA 3452/CITHEFOR, Université De Lorraine , Nancy , France and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fries
authors.affiliation: a EA 3452/CITHEFOR, Université De Lorraine , Nancy , France and.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gibaud
mesh_terms: D000464:Alginates / Q000737:chemistry*; D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000737:chemistry*; D015538:Nitrosation; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D026422:S-Nitrosoglutathione / Q000737:chemistry*; D026403:S-Nitrosothiols / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D000464:Alginates; D003692:Delayed-Action Preparations; D006603:Hexuronic Acids; D011108:Polymers; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D020723:Glucuronic Acid
keywords: Alginate; Crohn’s disease; nitric oxide; oral route; polymer