Pharmacokinetics and efficacy of orally administered polymeric chloroquine as macromolecular drug in the treatment of inflammatory bowel disease. Acta Biomater 2018 Dec;82:158-170
Date
10/21/2018Pubmed ID
30342282Pubmed Central ID
PMC6258327DOI
10.1016/j.actbio.2018.10.027Scopus ID
2-s2.0-85055279960 (requires institutional sign-in at Scopus site) 20 CitationsAbstract
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.
Author List
Kanvinde S, Chhonker YS, Ahmad R, Yu F, Sleightholm R, Tang W, Jaramillo L, Chen Y, Sheinin Y, Li J, Murry DJ, Singh AB, Oupický DAuthor
Yuri M. Sheinin MD, PhD Associate Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Administration, OralAnimals
Chloroquine
Citrobacter rodentium
Cytokines
Disease Models, Animal
Enterobacteriaceae Infections
Inflammatory Bowel Diseases
Male
Mice