Supramolecular nanofiber of indomethacin derivative confers highly cyclooxygenase-2 (COX-2) selectivity and boosts anti-inflammatory efficacy.

Herein, we report a facile method for converting carboxylate-containing indomethacin (Idm) into a cyclooxygenase-2 (COX-2) selective inhibitor via the amidation of an unnatural peptide sequence (Nal-Nal-Asp). The resulting indomethacin amides (i.e., Idm-Nal-Nal-Asp) have high selectivity for COX-2, and can self-assemble into a one-component supramolecular hydrogel that acts as a 'self-delivery' system for boosting anti-inflammatory efficacy. Self-assembled Idm-Nal-Nal-Asp hydrogel robustly inhibits COX-2 expression in lipopolysaccharide (LPS)-activated Raw 264.7 macrophages while also exhibits superior anti-inflammatory and antioxidant activities via reactive oxygen species (ROS)-related NF-κB and Nrf2/HO-1 pathways. Moreover, a rabbit model of endotoxin-induced uveitis (EIU) reveals that the Idm-Nal-Nal-Asp hydrogel outperforms clinically used 0.1 wt% diclofenac sodium eye drops in terms of in vivo anti-inflammatory efficacy via topical instillation route. As a rational approach to designing and applying COX-2 selective inhibitors, this work presents a simple method for converting non-selective nonsteriodal anti-inflammatory drugs (NSAIDs) into highly selective COX-2 inhibitors that can self-assemble into supramolecular hydrogel for anti-inflammation applications. [Display omitted] [ABSTRACT FROM AUTHOR]