Intra-articular (IA) glucocorticoids (GC) are commonly used for clinical management of both osteoarthritis and rheumatoid arthritis, but their efficacy is limited by the relatively short duration of action and associated side effects. To provide sustained efficacy and to improve the safety of GCs, we previously developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug. Serendipitously, we discovered that, by increasing the Dex content of the prodrug to unusually high levels, the aqueous solution of the polymeric prodrug becomes thermoresponsive, transitioning from a free-flowing liquid at 4 °C to a hydrogel at 30 °C or greater. Upon IA injection, the prodrug solution forms a hydrogel (ProGel-Dex) that is retained in the joint for more than 1 month, where it undergoes gradual dissolution, releasing the water-soluble polymeric prodrug. The released prodrug is swiftly internalized and intracellularly processed by phagocytic synoviocytes to release free Dex, resulting in sustained amelioration of joint inflammation and pain in rodent models of inflammatory arthritis and osteoarthritis. The low molecular weight (6.8 kDa) of the ProGel-Dex ensures rapid renal clearance once it escapes the joint, limiting systemic GC exposure and risk of potential off-target side effects. The present study illustrates the translational potential of ProGel-Dex as a potent opioid-sparing, locally delivered adjuvant analgesic for sustained clinical management of arthritis pain and inflammation. Importantly, the observed thermoresponsive properties of the prodrug establishes ProGel as a platform technology for the local delivery of a broad spectrum of therapeutic agents to treat a diverse array of pathological conditions.

关节内（IA）糖皮质激素（GC）通常用于骨关节炎和类风湿关节炎的临床治疗，但其疗效因作用持续时间相对较短和相关副作用而受到限制。为了提供持续的功效并提高GC的安全性，我们之前开发了一种基于N- (2-羟丙基)甲基丙烯酰胺(HPMA)共聚物的地塞米松(Dex)前药。偶然地，我们发现，通过将前药的 Dex 含量增加到异常高的水平，聚合物前药的水溶液变得具有热响应性，从 4°C 的自由流动液体转变为 30°C 或更高的水凝胶。注射 IA 后，前药溶液形成水凝胶 (ProGel-Dex)，在关节中保留超过 1 个月，并逐渐溶解，释放出水溶性聚合物前药。释放的前药被吞噬滑膜细胞迅速内化并在细胞内加工，释放游离的 Dex，从而持续改善炎症性关节炎和骨关节炎啮齿动物模型中的关节炎症和疼痛。ProGel-Dex 的低分子量 (6.8 kDa) 可确保一旦逸出关节后快速被肾脏清除，从而限制全身 GC 暴露和潜在脱靶副作用的风险。本研究说明了 ProGel-Dex 作为一种有效的阿片类药物节约型局部递送辅助镇痛药的转化潜力，可用于关节炎疼痛和炎症的持续临床管理。重要的是，观察到的前药的热响应特性使 ProGel 成为一种平台技术，用于局部递送广谱治疗剂以治疗多种病理状况。