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

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.

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

“…Finally, oral administration of a non degradable poly meric form of chloroquine is under investigation for the treatment of inflammatory bowel diseases. Clinical data suggest that this formulation can suppress the production of IL6 and IL1β and upregulate the production of IL2 in the intestine 153 as a result of altered mucosal immune homeostasis.…”

Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine

“…This strategy has proven useful for the delivery of small molecule drugs for cancer and neurological diseases, and there are several candidates in clinical trials [ 98 ]. To our knowledge, only a single example of a polymer prodrug of HCQ evaluated in vivo has been published, and it demonstrated substantially better efficacy and lower toxicity compared to unformulated HCQ in a mouse model of colitis [ 69 ].…”

Non-autophagy role of Atg5 and NBR1 in unconventional secretion of IL-12 prevents gut dysbiosis and inflammation

“…A1. These reagents have been used with some clinical efficacy in IBD patients and animal models of IBD (Goenka, Kochhar et al, 1996, Kanvinde, Chhonker et al, 2018, Nagar, Ranade et al, 2014, Park, Jang et al, 2019. It is unclear if these effects were due to IL-12 regulation but targeting IL-12, specifically, the IL-12p40 subunit that is shared with IL-23, has also proven beneficial for some IBD patients (Feagan, Sandborn et al, 2016, Moschen et al, 2019, Sands, Sandborn et al, 2019.…”