(484f) Controlled Release of Anti-Tumor Necrosis Factor-Alpha siRNA From Biodegradable Polymeric Microparticles

Temporomandibular joint (TMJ) disorders are a heterogeneous group of diseases that cause painful, progressive joint degeneration. Effective pain reduction and restoration of TMJ function remain unmet challenges. Intra-articular injections of corticosteroids and hyaluronic acid are currently used to treat pain, but are complicated by rapid clearance of injected agents, so that frequent injections are needed, increasing the risk of iatrogenic injury. There is a need for controlled release systems for the TMJ. We have previously reported the in vivo biocompatibility of blank poly(DL-lactic-co-glycolic acid) (PLGA)-based microparticles (MPs) injected intra-articularly in the rat TMJ. In this work, we report the application of PLGA MPs for controlled release of a model anti-inflammatory TMJ therapeutic agent: small interfering RNA antagonizing tumor necrosis factor-α (anti-TNF siRNA). PLGA MPs synthesized using an established double emulsion solvent extraction technique were loaded with varying amounts of rat anti-TNF siRNA (1 nmol, 5 nmol) complexed with polyethyleneimine (PEI) as a transfecting agent. Complexes with N:P ratios of 16:1 and 8:1 were selected based on previous results indicating successful gene silencing. Anti-TNF siRNA was selected as a potential TMJ therapeutic based on its successful intra-articular application in arthritic knee models. Excellent encapsulation efficiency was achieved for all groups. Both siRNA and PEI release were measured and distinct release profiles were observed from each MP formulation over 28 days, with minimal burst release (10-40% of the total anti-TNF siRNA-PEI complexes loaded) lasting for the first 12h. This successful sustained release with minimal burst release underscores the exciting potential of PLGA MP formulations as the basis for an intra-articular controlled release system for treating TMJ disorders. Future studies will characterize these siRNA-PEI-loaded MPs in a TMJ disorder model, with the potential to greatly improve TMJ therapeutics.