Pharmacokinetics and efficacy of orally administered polymeric chloroquine as macromolecular drug in the treatment of inflammatory bowel disease

Shrey Kanvinde, Yashpal Singh Chhonker, Rizwan Ahmad, Fei Yu, Richard Sleightholm, Weimin Tang, Lee Jaramillo, Yi Chen, Yuri Sheinin, Jing Li, Daryl J Murry, Amar B. Singh, David Oupicky

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)158-170
Number of pages13
JournalActa Biomaterialia
Volume82
DOIs
StatePublished - Dec 2018

Keywords

  • Chloroquine
  • Citrobacter rodentium
  • Colitis
  • Inflammatory bowel disease
  • Oral administration
  • Pharmacokinetics
  • Polymeric drug

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

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