Surface modified cationic PLGA microparticles as long-acting injectable carriers for intra-articular small molecule...

Controlled local delivery of therapeutics (small molecule drug crystals or biologics) for knee-associated diseases such as osteoarthritis necessitates patient compliance, ensuring that the injected depot does not trigger local tissue inflammation and immune responses. A local drug delivery strategy that releases drug at a controlled rate while ensuring minimal tolerability issues at the injection site would be an appealing paradigm in intra-articular (IA) therapies. Herein, we report the formulation development and characterization of surface modified PLGA microparticles (MPs) through the surface integration of a cationic lipid, DOTAP (1,2-Dioleoyl-3-trimethylammonium propane). Following IA administration, these particles are able to interact with anionic synovial fluid glycosaminoglycans (GAGs) to form an in-situ surface coating in the knee joint, thereby reducing the depot-associated local inflammatory response. The formulated microparticles were about 10-40 µm in size range, with a +19 to +33 mV overall surface charge after DOTAP lipid surface integration. These particles showed preferential surface adhesion with endogenous anionic GAGs (e.g., hyaluronic acid) due to electrostatic interactions in vitro, and approximately 65% of the model drug triamcinolone acetonide (TCA) was released after 10 weeks in simulated synovial fluid. The uncoated and DOTAP-coated PLGA microparticles had no effect on mouse osteoblast MC3T3 cell viability and human macrophage inflammatory response. Further, DOTAP-coated particles showed a marginal decrease in pro-inflammatory cytokines in naïve rats following knee injection. Together, the results suggest that surface-modified PLGA particles may have promising potential as delivery carriers for long-acting injectables.