Xu Long, Yang Yidi, Zhao Mingying, Gao Wenxia, Zhang Hai, Li Sai, He Bin, Pu Yuji
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
J Mater Chem B. 2018 Feb 21;6(7):1076-1084. doi: 10.1039/c7tb02479g. Epub 2018 Feb 2.
Stimuli-responsive polymeric drug delivery systems are of great interest in anticancer research. Here, a reactive oxygen species (ROS)-responsive prodrug was prepared by thioketal linkage of poly(ethylene glycol) (PEG) and the anticancer drug doxorubicin (DOX). The ROS-responsive property of the prodrug was confirmed by dynamic light scattering and H NMR. The prodrug was then used as a drug carrier to further load DOX, to form a DOX-loaded prodrug micelle, which showed dual ROS and pH-responsive release behaviors. The prodrug micelle exhibited rapid intracellular uptake. Interestingly, the in vitro anticancer activity of the ROS-responsive prodrug micelle was better than that of the DOX-loaded prodrug micelle because of its faster cellular uptake and better bioavailability. However, both the ROS-responsive prodrug and drug-loaded prodrug micelles showed better anticancer efficacy than a non-responsive DOX-loaded poly(ethylene glycol)-block-polycaprolactone (PEG2k-PCL5k) micelle. Consistent results were obtained in in vivo animal experiments as the antitumor efficacy of the prodrug micelle was superior to that of the DOX-loaded prodrug micelle. Both micelles showed negligible systemic toxicity in vivo.
刺激响应性聚合物药物递送系统在抗癌研究中备受关注。在此，通过聚乙二醇（PEG）与抗癌药物阿霉素（DOX）的硫酮键合制备了一种活性氧（ROS）响应性前药。通过动态光散射和氢核磁共振证实了前药的ROS响应特性。然后将该前药用作药物载体进一步负载DOX，形成负载DOX的前药胶束，其表现出ROS和pH双重响应释放行为。前药胶束表现出快速的细胞内摄取。有趣的是，ROS响应性前药胶束的体外抗癌活性优于负载DOX的前药胶束，因为其细胞摄取更快且生物利用度更高。然而，ROS响应性前药和负载药物的前药胶束均显示出比无响应的负载DOX的聚乙二醇-嵌段-聚己内酯（PEG2k-PCL5k）胶束更好的抗癌效果。在体内动物实验中获得了一致的结果，因为前药胶束的抗肿瘤功效优于负载DOX的前药胶束。两种胶束在体内均显示出可忽略不计的全身毒性。
