PLGA Based Drug Carriers for Treatment of Osteoarthritis

Abstract

Osteoarthritis (OA) has affected nearly 22-39% of the Indian population and remains one of the most common musculoskeletal disorders that affects articular joints. Post-traumatic osteoarthritis, which develops following trauma to the knee joint, can lead to severe disability and morbidity in otherwise healthy individuals. The current standard of care for osteoarthritis (OA) primarily revolves around symptomatic relief with total knee arthroplasty at the end stage of the disease. Translation of many disease-modifying OA drugs (DMOADs) stagnates due to low bioavailability at the affected site, necessitating multiple injections and decreased patient compliance. Our project's primary aim was to encapsulate DMOADs in a polymer matrix to assess their tuneability and evaluate the drugs' potency in preventing and treating OA. Potential disease-modifying strategies widely researched are the modulation of autophagy and senescence pathways. Rapamycin and Nordihydroguaiaretic acid (NDGA) hold promise as a potent DMOAD in OA as they induce autophagy and prevent senescence. NDGA is also a potent ROS scavenger and can reduce oxidative stress in OA. Although intra-articular injections of these drugs can ensure delivery of large doses in the knee joint, lymphatic clearance of drug can still rapidly reduce the drug concentration below the therapeutic levels making the translation of these drugs difficult. Here, we have synthesized drug-loaded poly (lactic-co-glycolic acid) microparticles (MPs) that induced autophagy, prevented senescence, and sustained sGAG production in primary human articular chondrocytes from OA patients. These MPs were potent, nontoxic, and exhibited prolonged retention time (up to 35 days) in mice joints. Intra-articular delivery of these MPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen in the regular diet and high fat-fed obese mice models. Together, our studies demonstrate the feasibility of using rapamycin-loaded and NDGA-loaded MPs as potential clinically translatable therapies to prevent and treat post-traumatic osteoarthritis.