Pharmacokinetics and efficacy of orally administered polymeric chloroquine as macromolecular drug in the treatment of inflammatory bowel disease. (December 2018)

• Record Type: Journal Article
• Authors: Kanvinde, Shrey; Chhonker, Yashpal Singh; Ahmad, Rizwan; Yu, Fei; Sleightholm, Richard; Tang, Weimin; Jaramillo, Lee; Chen, Yi; Sheinin, Yuri; Li, Jing; Murry, Daryl J.; Singh, Amar B.; Oupický, David
• Is Part Of: Acta biomaterialia. Volume 82(2018)
• Page Start: 158
• Page End: 170
• Publication Date: 2018-12
• Subjects: Inflammatory bowel disease -- Colitis -- Citrobacter rodentium -- Chloroquine -- Oral administration -- Polymeric drug -- Pharmacokinetics; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2018.10.027
• Languages: English
• ISSNs: 1742-7061

Abstract

Graphical abstract: Abstract: Inflammatory bowel disease is a chronic inflammation of the gastrointestinal tract with poor understanding of its pathogenesis and no effective cure. The goal of this study was to evaluate the feasibility of orally administered non-degradable polymeric chloroquine (pCQ) to locally reduce colon inflammation. The pCQ was synthesized by radical copolymerization of N-(2-hydroxypropyl)methacrylamide with methacryloylated hydroxychloroquine (HCQ). The anti-inflammatory activity of orally administered pCQ versus HCQ was tested in a mouse model of colitis induced by Citrobacter rodentium (C. rodentium) . Single-dose pharmacokinetic and biodistribution studies performed in the colitis model indicated negligible systemic absorption (p ≤ 0.001) and localization of pCQ in the gastrointestinal tract. A multi-dose therapeutic study demonstrated that the localized pCQ treatment resulted in significant reduction in the colon inflammation (p ≤ 0.05). Enhanced suppression of pro-inflammatory cytokines IL-6 (p ≤ 0.01) and IL1-β and opposing upregulation of IL-2 (p ≤ 0.05) recently reported to be involved in downstream anti-inflammatory events suggested that the anti-inflammatory effects of the pCQ are mediated by altering mucosal immune homeostasis. Overall, the reported findings demonstrate a potential of pCQ as a novel polymer therapeutic option in inflammatory bowel disease with the potential of local effects and minimized systemic toxicity.