Long-acting triamcinolone acetonide prodrug microcrystals for sustained intra-articular treatment of osteoarthritis

Intra-articular injection of triamcinolone acetonide (TA) is widely used to treat osteoarthritis (OA), a prevalent chronic joint disease imposing substantial clinical and socioeconomic burdens. However, current long-acting TA formulations suffer from limited therapeutic duration or require invasive administration, compromising patient compliance. To address this challenge, we developed two TA prodrug microcrystals (MCs)-PKTA and PETA-by conjugating hydrophobic palmitoyl groups via acid-sensitive ketal or enzymatically cleavable ester linkages, respectively. Both formulations exhibited high drug loading (>60%) and markedly sustained in vitro release, resulting in prolonging joint residence time. In a rat destabilization of the medial meniscus OA model, a single low-dose injection of either prodrug MCs maintained therapeutic efficacy for up to 4-6 weeks, compared to <2 weeks for clinical TA MCs administered at a fourfold higher dose. Notably, despite the reduced dosing, PKTA and PETA MCs achieved prolonged intra-articular retention with reduced systemic TA exposure compared with conventional TA MCs. This sustained benefit manifested as prolonged pain and inflammation suppression, preserved type II collagen expression, attenuated MMP-13 levels, and improved subchondral bone microarchitecture. Notably, PKTA MCs demonstrated superior therapeutic performance throughout the evaluation period. Histological analyses confirmed significant attenuation of cartilage degeneration and synovitis without systemic toxicity. These findings establish PKTA MCs as a promising minimally invasive, long-acting platform for OA management.