Zhao Yong-Jiang, Wei Wei, Su Zhi-Guo, Ma Guang-Hui
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, POBox353, Beijing 100190, China.
Int J Pharm. 2009 Sep 8;379(1):90-9. doi: 10.1016/j.ijpharm.2009.06.013. Epub 2009 Jun 18.
Poly (ethylene glycol)s (PEGs) are potential drug carriers for improving the therapeutic index of anticancer agents. In this work, a novel methodology for constructing PEG prodrug of anthracycline anticancer drugs was developed based on N-Mannich base of salicylamide and its 2-acyloxymethylated derivative. The resultant conjugates first subjected to in vitro hydrolysis testing, which revealed the release behavior of newly synthesized PEG prodrugs could be adjusted by the status of 2-hydroxy group of salicylamide. These PEG prodrugs also demonstrated superior cytotoxicity in antiproliferative assay. O-blocked doxorubicin prodrug with PEG20k as carrier was selected for further in vivo assessments and presented longer circulating life in pharmacokinetic experiment. This high molecular prodrug was also found to be more efficacious against S-180 xenografted tumor than equivalent amount of doxorubicin.
聚乙二醇（PEGs）是用于提高抗癌药物治疗指数的潜在药物载体。在这项工作中，基于水杨酰胺的N-曼尼希碱及其2-酰氧基甲基化衍生物，开发了一种构建蒽环类抗癌药物PEG前药的新方法。所得共轭物首先进行体外水解测试，结果表明新合成的PEG前药的释放行为可通过水杨酰胺2-羟基的状态进行调节。这些PEG前药在抗增殖试验中也表现出优异的细胞毒性。选择以PEG20k为载体的O-封闭阿霉素前药进行进一步的体内评估，其在药代动力学实验中显示出更长的循环寿命。还发现这种高分子前药对S-180异种移植肿瘤的疗效比等量的阿霉素更高。
