Jia Zhenshan, Zhao Gang, Wei Xin, Kong Dexuan, Sun Yuanyuan, Zhou You, Lele Subodh M, Fehringer Edward V, Garvin Kevin L, Goldring Steven R, Wang Dong
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Control Release. 2020 Aug 10;324:560-573. doi: 10.1016/j.jconrel.2020.05.028. Epub 2020 May 20.
Despite their notorious adverse effects, glucocorticoids (GC, potent anti-inflammatory drugs) are used extensively in clinical management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. To achieve a sustained therapeutic efficacy and reduced toxicities, macromolecular GC prodrugs have been developed with promising outcomes for the treatment of RA. Fine-tuning the activation kinetics of these prodrugs may further improve their therapeutic efficacy and minimize the off-target adverse effects. To assess the feasibility of this strategy, five different dexamethasone (Dex, a potent GC)-containing monomers with distinctively different linker chemistries were designed, synthesized, and copolymerized with N-(2-hydroxypropyl) methacrylamide (HPMA) to obtain 5 macromolecular Dex prodrugs. Their Dex releasing rates were analyzed in vitro and shown to display a wide spectrum of activation kinetics. Their therapeutic efficacy and preliminary toxicology profiles were assessed and compared in vivo in an adjuvant-induced arthritis (AA) rat model in order to identify the ideal prodrug design for the most effective and safe treatment of inflammatory arthritis. The in vivo data demonstrated that the C3 hydrazone linker-containing prodrug design was the most effective in preserving joint structural integrity. The results from this study suggest that the design and screening of different activation mechanisms may help to identify macromolecular prodrugs with the most potent therapeutic efficacy and safety for the management of inflammatory arthritis.
尽管糖皮质激素（GC，强效抗炎药物）存在众所周知的不良反应，但仍广泛用于类风湿性关节炎（RA）和其他慢性炎症性疾病的临床治疗。为了实现持续的治疗效果并降低毒性，已开发出大分子GC前药，在治疗RA方面取得了有前景的成果。微调这些前药的激活动力学可能会进一步提高其治疗效果，并将脱靶不良反应降至最低。为了评估该策略的可行性，设计、合成了五种具有明显不同连接基化学结构的含地塞米松（Dex，一种强效GC）的单体，并将其与N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚，以获得5种大分子Dex前药。对它们的Dex体外释放速率进行了分析，结果显示其具有广泛的激活动力学。在佐剂诱导的关节炎（AA）大鼠模型中对它们的治疗效果和初步毒理学概况进行了体内评估和比较，以确定用于最有效和安全治疗炎性关节炎的理想前药设计。体内数据表明，含C3腙连接基的前药设计在保持关节结构完整性方面最有效。本研究结果表明，设计和筛选不同的激活机制可能有助于确定对炎性关节炎治疗具有最有效治疗效果和安全性的大分子前药。
