Peptide-grafted nanogels for sustained endothelin and bradykinin blockade in osteoarthritis

Osteoarthritis (OA) is a widespread cause of physical disability and chronic pain, yet it lacks a pharmacological cure due to the difficulty of delivering drugs to avascular cartilage. We recently developed peptide-grafted nanogels for intra-articular injection that were well tolerated in vivo in healthy equine joints. Hence, this study reports the pharmaceutical aspects of this drug delivery system, which is based on biopolymeric nanohydrogels (nanogels, NG) for the localized, sustained delivery of two peptide antagonists of endothelin-1 (ETA) and bradykinin (BKB1), namely BQ123 and R954. Chitosan and hyaluronic acid were first functionalized with BQ123 and R954, respectively (CH-BQ123 and HA-R954), and subsequently used to synthesize nanogels via ionic gelation (NG BQ123 and NG R954). Peptide-conjugated NG were characterized for stability, peptide release in human synovial fluid, cytocompatibility, and biological efficacy in vitro in human chondrocytes. NG BQ123 and NG R954 showed slow, sustained release in synovial fluid for up to three months. Both were biocompatible with human chondrocytes and rapidly internalized by the cells. Notably, in vitro therapeutic effects were observed after only seven days of treatment, attributed to the slow peptide release reducing nitric oxide (NO) and Cyclooxygenase-2 expression. This study demonstrates a nanogel platform enabling localized, sustained peptide delivery, supporting the potential therapeutic use of NG BQ123 and NG R954 in OA treatment.