The Development of Four-Arm PEG-Based Thermoresponsive Dexamethasone Prodrugs for the Treatment of Osteoarthritis Pain

Thermoresponsive polymeric prodrugs represent a promising strategy for localized and sustained in vivo drug delivery. In this work, two polyethylene glycol (PEG)-based dexamethasone (Dex) prodrugs with different Dex contents were synthesized using a four-arm PEG scaffold. Prodrug 1, containing four Dex molecules, showed high aqueous solubility but no thermoresponsive gelation behavior. In contrast, eight-Dex Prodrug 2 exhibited temperature-dependent aggregation and formed hydrogels in aqueous media. The viscosity of the Prodrug 2 hydrogel was reduced by introducing 10% ethanol as a cosolvent, enabling an injectable formulation that rapidly forms a hydrogel depot upon contact with aqueous media. The hydrogel provides gradual Dex release via the cleavage of the acid-labile hydrazone bond linking Dex to the PEG. In a monosodium iodoacetate (MIA)-induced osteoarthritis (OA) pain model, intra-articular (IA) injection of Prodrug 2 produced rapid and sustained pain relief for up to 28 days. These findings indicate that the hydrogel-forming four-arm PEG-based Dex prodrug offers a potentially effective approach for prolonged local corticosteroid (CS) delivery, applicable to the treatment of many local pathologies, including OA and OA pain.