Redox-responsive self-assembly polymeric micelles based on mPEG-β-cyclodextrin and a camptothecin prodrug as drug release carriers  

基于mPEG-β-环糊精和喜树碱前药的还原敏感自组装胶束作为药物释放载体

作　　者：Yiben Lu Miao Zhang Yongjun Zheng Xinyu Hou Muye He Kaiyan Lou Feng Gao 陆益奔;张苗;郑永军;侯昕宇;贺牧野;楼开炎;高峰(华东理工大学上海功能性材料化学重点实验室,上海200237;华东理工大学上海新药设计重点实验室,上海200237;华东理工大学药学院药剂学系,上海200237)

机构地区：[1]Shanghai Key Laboratory of Functional Materials Chemistry,East China University of Science and Technology,Shanghai 200237,China [2]Shanghai Key Laboratory of New Drug Design,East China University of Science and Technology,Shanghai 200237,China [3]Department of Pharmaceutics,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2021年第12期941-955,共15页中国药学（英文版）

基　　金：National Key Research and Development Program of China (Grant No. 2019YFA0904800);Science and Technology Commission of Shanghai Municipality (Grant No. 11DZ2260600 and 10DZ2220500);Shanghai Natural Science Fund (Grant No. 20ZR1414700)。

摘　　要：Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic drug in chemotherapy but often face challenging synthesis and purification of functionalized biocompatible polymer materials and low drug loading efficiency. In the present study, we reported a novel redox-responsive self-assembly polymeric micelle system, mPEG-β-CD/Ad-SS-CPT, to achieve high loading efficiency and selective delivery of camptothecin(CPT) in a reductive environment inside cancer cells. The host-guest supramolecular micelles utilized a simple β-CD modified PEG, mPEG-β-cyclodextrin(mPEG-β-CD), as the polymeric host with the ease of synthesis and purification. The guest prodrug Ad-SS-CPT contained the disulfide bond as the redox sensitivity group. The selective cleavage of disulfide bond and subsequent drug release in a reductive environment could potentially reduce system toxicity and improve the therapeutic outcome of CPT. In vitro studies showed that the micelles exhibited excellent cytotoxicity against He La cells comparable to the free drug. The host-guest polymeric micelles also showed great potentials for multi-drug co-delivery. Collectively, our current findings provided a general and convenient approach to design drug delivery systems based on stimuli-responsive polymeric micelles for disease treatment.基于聚合物胶束的刺激响应性药物递送系统可以实现药物的控制释放,从而改善治疗效果,降低药物在化疗中不必要的系统毒性和副作用,但生物相容性高分子材料的功能化往往面临着合成、纯化难度大以及载药率低的挑战。本文报道了一种新型的还原敏感自组装聚合物胶束系统mPEG-β-CD/Ad-SS-CPT,实现了喜树碱(CPT)的高负载,以及在还原性环境下的选择性药物释放。主客体超分子聚合物胶束利用聚乙二醇修饰的β-环糊精,即mPEG-β-CD作为聚合物的主体,易于合成和纯化;连有金刚烷(Ad)与CPT的前药Ad-SS-CPT作为客体,所含有的二硫键作为还原敏感性功能基团。二硫键的选择性断裂和药物在还原性环境中的释放,有可能降低CPT的系统毒性,并提高疗效。体外研究表明,mPEG-β-CD/Ad-SS-CPT胶束对HeLa细胞的细胞毒性与游离药物相当。基于主客体的聚合物胶束在多药协同给药方面也显示出巨大的潜力,为设计刺激响应性药物递送系统提供一种通用、方便的方法。

关 键 词：mPEG-β-cyclodextrin Camptothecin prodrug Self-assembled micelles Redox-responsive SUPRAMOLECULAR 

分 类 号：R943[医药卫生—药剂学]