Nordihydroguaiaretic acid microparticles are effective in the treatment of osteoarthritis

Several disease-modifying osteoarthritis (OA) drugs have emerged, but none have been approved for clinical use due to their systemic side effects, short half-life, and rapid clearance from the joints. Nordihydroguaiaretic acid (NDGA), a reactive oxygen species (ROS) scavenger and autophagy inducer, could be a potential treatment for OA. In this report, we show for the first time that sustained delivery of NDGA through polymeric microparticles maintains therapeutic concentrations of drug in the joint and ameliorates post-traumatic OA (PTOA) in a mouse model. In vitro treatment of oxidatively stressed primary chondrocytes from OA patients using NDGA-loaded poly(lactic- co -glycolic acid) (PLGA) microparticles (NDGA-MP) inhibited 15-lipoxygenase, induced autophagy, prevented chondrosenescence, and sustained matrix production. In vivo intra-articular delivery of NDGA-MP was non-toxic and had prolonged retention time (up to 35 days) in murine knee joints. Intra-articular therapy using NDGA-MP effectively reduced cartilage damage and reduced pain in the surgery-induced PTOA mouse model. Our studies open new avenues to modulate the immune environment and treat post-traumatic OA using ROS quenchers and autophagy inducers. Sustained delivery of NDGA via polymeric microparticles maintains therapeutic levels in joints, reduces cartilage damage, and alleviates post-traumatic osteoarthritis (PTOA) in mice through ROS modulation and autophagy induction.