Extended osteoarthritis pain relief with neosaxitoxin using alginate-core polymeric microparticles

Abstract

Osteoarthritis (OA) is a leading cause of chronic pain, affecting millions worldwide. Conventional pharmacological treatments provide only short-term relief and pose risks with long-term use, highlighting the need for safer, sustained analgesic strategies. Voltage-gated sodium channels (Na_V), particularly Na_V1.7, are key mediators of OA pain and represent a promising therapeutic target. Neosaxitoxin (NSTX), a potent site-1 sodium channel blocker (S1SCB), exhibits high affinity for Na_V1.7. Clinical studies demonstrate that subcutaneous administration of NSTX can safely block sensory pain in healthy individuals, but its anesthetic effect is short-lived, limiting its clinical utility for OA. Here, we report the first use of NSTX for OA pain relief with a local intra-articular (IA) delivery approach. A low dose (10 pg) produced effective pain relief in a post-traumatic OA mouse model, as assessed by knee hyperalgesia testing. However, the effect persisted for only a few hours even with a 100-fold higher dose, highlighting the need for sustained delivery. To prolong this short-lived pain relief and overcome the challenges of encapsulating small, hydrophilic S1SCBs like NSTX, we developed a sustained-release platform using alginate–poly(lactic-co-glycolic acid) microparticles (AlgPLGA-MPs). Incorporation of a negatively charged alginate core in the inner aqueous phase enhanced NSTX encapsulation through electrostatic interactions and minimized burst release. IA injection of NSTX encapsulated AlgPLGA-MP in a murine OA model produced significant pain relief for up to one week. To further prolong joint residence time, the microparticle surface was functionalized with cationic avidin (AvAlgPLGA-MP) that reversed the net surface charge from anionic to cationic. This modification promoted electrostatic binding to negatively charged synovial matrix components and prolonged intra-joint retention time, while maintaining biocompatibility. Together, these results establish NSTX as a highly potent analgesic for chronic OA pain and present alginate-core PLGA microparticles as a safe and effective sustained-release platform. This delivery system holds broad translational potential for other small, hydrophilic analgesics and therapeutic agents.