Thermoresponsive polymeric dexamethasone prodrug for arthritis pain.
Thermoresponsive polymeric dexamethasone prodrug for arthritis pain.
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DOI：
10.1016/j.jconrel.2021.10.007
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发表时间：
2021-11-10
期刊：
影响因子：
--
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Zhao G;Ren R;Wei X;Jia Z;Chen N;Sun Y;Zhao Z;Lele SM;Zhong HA;Goldring MB;Goldring SR;Wang D
关节内（IA）糖皮质激素（GC）通常用于骨关节炎和类风湿性关节炎的临床管理，但其疗效受到相对较短的作用持续时间和相关副作用的限制。为了提供持续的疗效并提高GC的安全性，我们先前开发了基于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温度响应性，从4°C下的自由流动液体转变为30°C或更高温度下的水凝胶。在IA注射后，前药溶液形成水凝胶（ProGel-Dex），其在关节中保留超过1个月，在那里其经历逐渐溶解，释放水溶性聚合物前药。释放的前药迅速内化并被吞噬细胞滑膜细胞细胞胞内加工，释放游离Dex，从而持续改善啮齿动物炎症性关节炎和骨关节炎模型的关节炎症和疼痛。ProGel-Dex的低分子量（6.8 kDa）可确保其在脱离关节后快速肾清除，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样物质保留，局部递送的辅助镇痛剂用于关节炎疼痛和炎症的持续临床管理的转化潜力。重要的是，所观察到的前药的温度响应特性确立了ProGel作为用于局部递送广谱治疗剂以治疗多种病理状况的平台技术。一种温敏性聚合地塞米松前体药物，可持续缓解关节炎疼痛和炎症，且无明显的糖皮质激素相关毒性。
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. A thermoresponsive polymeric dexamethasone prodrug provides sustained resolution of arthritis pain and inflammation without apparent glucocorticoid-associated toxicity.
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