Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; Ensign Pharmaceutical, Inc., Omaha, NE 68106, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Control Release. 2021 Nov 10;339:484-497. doi: 10.1016/j.jconrel.2021.10.007. Epub 2021 Oct 12.
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）常用于治疗骨关节炎和类风湿关节炎，但由于作用时间相对较短以及相关副作用，其疗效受到限制。为了提供持续的疗效并提高 GC 的安全性，我们之前开发了一种 N-(2-羟丙基)甲基丙烯酰胺（HPMA）共聚物载药的地塞米松（Dex）前药。偶然的是，我们发现，通过将前药中 Dex 的含量增加到异常高的水平，聚合物前药的水溶液会变成温敏的，从 4°C 时的自由流动液体转变为 30°C 或更高温度时的水凝胶。IA 注射后，前药溶液形成水凝胶（ProGel-Dex），在关节中保留超过 1 个月，在关节中逐渐溶解，释放出水溶性聚合物前药。释放的前药被吞噬性滑膜细胞迅速内化并在细胞内处理，释放出游离的 Dex，从而在炎症性关节炎和骨关节炎的啮齿动物模型中持续改善关节炎症和疼痛。ProGel-Dex 的低分子量（6.8 kDa）确保一旦它从关节逃逸，就会迅速通过肾脏清除，从而限制了全身 GC 的暴露和潜在的非靶标副作用的风险。本研究说明了 ProGel-Dex 作为一种有效的阿片类药物节约型、局部递药的辅助镇痛剂的转化潜力，可用于持续治疗关节炎疼痛和炎症。重要的是，前药的温敏特性表明 ProGel 是一种平台技术，可用于局部递药治疗各种病理状况的广泛治疗剂。
