(T1330-01-01) ROS-Responsive Mucoadhesive Pro-drug with Mesalazine for Curing Inflammatory Bowel Disease

Purpose: Inflammatory bowel disease (IBD) is associated with excessive Reactive Oxygen Species (ROS) leading to oxidative stress and inflammatory signaling pathway. Mesalazine is the most prescribed medication for curing IBD, and it functions as an inhibitor of COX-1 and COX-2. This inhibition leads to the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). However, without delivery system, the majority of Mesalazine is absorbed in the stomach and small intestine, resulting in only 20% of the administered dose reaching the colon. In this work, we developed a mucoadhesive ROS responsive pro-drug for the treatment of IBD.

Methods: Mesalazine (M) was conjugated to Glycol chitosan (GC) by thioketal (TK) linker thioketal (TK), which is ROS-responsive. We tested its anti-inflammatory effect in vitro and DSS-induced mice in vivo.

Results: We demonstrated that the GC-M pro-drug could alleviate inflammation with scavenging both NO and ROS from LPS-stimulated RAW 264.7 macrophages, which is known to produce excessive ROS. Mucoadhesive properties of glycol chitosan was explored by FITC-labeling in vivo. The orally administered GC-M pro-drug recovered the body weight and colon length in DSS-induced mice model. Moreover, compared to DSS-induced group, GC-TK-M pro-drug group diminished colonic proinflammatory cytokines in mRNA and protein levels.

Conclusion: The Glycol chitosan–thioketal–Mesalazine (GC-M) pro-drug can be designed to release the conjugated Mesalazine in response to the presence of a ROS environment in IBD animal model.

References: 1. Neurath, M. F. Current and emerging therapeutic targets for IBD. Nature Reviews Gastroenterology & Hepatology 14, 269-278 (2017).
2. Nielsen, O. H. & Munck, L. K. Drug Insight: aminosalicylates for the treatment of IBD. Nature Clinical Practice Gastroenterology & Hepatology 4, 160-170 (2007).
3. Rinaldi, A. et al. Applications of the ROS-Responsive Thioketal Linker for the Production of Smart Nanomedicines. Polymers 14 (2022).

Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number NRF-2022R1A4A1030421, NRF-2020R1A2C3005834) and by the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean government (grant number: KFRM24A0105L1).