Center of Advanced Elastomer Materials, State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.
Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.
Macromol Biosci. 2020 Sep;20(9):e2000116. doi: 10.1002/mabi.202000116. Epub 2020 Jun 30.
Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) for relieving inflammatory reactions can lead to severe side effects. It is of great importance to configure new dosing strategies for alleviating the side effects of NSAIDs. In this work, an enzyme-responsive anti-inflammatory prodrug capable of generating indomethacin upon the trigger of inflammation is developed. A monomer is first prepared after the esterification of carboxyl groups of indomethacin by hydroxyl groups of N-(2-hydroxyethyl) acrylamide. Then, a polymer prodrug, with indomethacin linked through ester bonds on the side chain, is synthesized by free radical polymerization of the monomer. The therapeutic drug component can be triggered to release from the prodrug under the stimulation of cholesterol esterase, mimicking the inflammation environment. On the contrary, there is only a small amount of drug released in the absence of the enzyme. Therefore, the drug can be triggered to release under the stimulation of an environment mimicking inflammation. Furthermore, the in vitro studies at the cellular level indicate that the enzyme-responsive prodrug can efficiently relieve inflammatory responses induced by lipopolysaccharide in RAW264.7 macrophage cells while indicating no cytotoxicity.
长期使用非甾体抗炎药（NSAIDs）缓解炎症反应会导致严重的副作用。因此，配置缓解 NSAIDs 副作用的新剂量策略非常重要。在这项工作中，开发了一种酶响应的抗炎前药，能够在炎症触发时生成吲哚美辛。首先通过吲哚美辛的羧基与 N-(2-羟乙基)丙烯酰胺的羟基进行酯化反应制备单体。然后，通过单体的自由基聚合合成侧链通过酯键连接吲哚美辛的聚合物前药。在胆固醇酯酶的刺激下，治疗药物成分可以从前药中触发释放，模拟炎症环境。相反，在没有酶的情况下，只有少量药物释放。因此，药物可以在模拟炎症的环境刺激下触发释放。此外，细胞水平的体外研究表明，酶响应前药能够有效缓解 RAW264.7 巨噬细胞中脂多糖诱导的炎症反应，同时没有细胞毒性。
