State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines, College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Control Release. 2018 Mar 28;274:56-68. doi: 10.1016/j.jconrel.2018.01.034. Epub 2018 Feb 2.
Prodrug-based stimuli-responsive vectors have emerged as highly promising platform. Inspired by the fact that antioxidant systems including glutathione (GSH) make cancer cells adapt to oxidative stress and play a role in the inactivation of alkylating agents like chlorambucil (CHL) inside tumor cells, while arylboronic acid could transform into GSH depleting agent quinone methide (QM) upon degradation by reactive oxygen species (ROS) over-expressed in tumor cells, a ROS-responsive nanoprodrug (denoted by PPAHC) of CHL was established by integrating CHL into diols-containing hydrophilic polymer with self-immolative linker 4-(hydroxymethyl)phenylboronic acid (HPBA). The prodrug could form core-shell nanoparticle and possess high stability during storage. Drug release profile of PPAHC nanoprodrug demonstrated that nature CHL could be quickly released from PPAHC nanoprodrug in the presence of hydrogen peroxide (HO). Moreover, PPAHC nanoprodrug showed improved therapeutic efficiency compared to CHL via anti-proliferative study and cell apoptosis assay. Further measurement of GSH content and ROS levels in tumor cells suggested that the synergistic impact resulted from QM-mediated GSH reduction and CHL-induced further oxidative stress insults to tumor cells. In vivo tumor suppression effect and biocompatibility indicated the superiorities of PPAHC nanoprodrug. Accordingly, PPAHC provides a new approach as a ROS-responsive CHL delivery system and has a great potential for cancer therapy.
前药型刺激响应载体已成为极具前景的平台。受以下事实的启发：包括谷胱甘肽（GSH）在内的抗氧化系统使癌细胞适应氧化应激，并在肿瘤细胞内烷化剂如苯丁酸氮芥（CHL）的失活中发挥作用，而芳基硼酸在肿瘤细胞中过表达的活性氧（ROS）降解后可转化为 GSH 耗竭剂醌甲（QM），我们通过将 CHL 整合到含有自毁性连接子 4-（羟甲基）苯硼酸（HPBA）的二醇亲水聚合物中，构建了一种 CHL 的 ROS 响应性纳米前药（记为 PPAHC）。该前药在储存过程中可以形成核壳纳米颗粒，具有高稳定性。PPAHC 纳米前药的药物释放曲线表明，在过氧化氢（HO）存在下，天然 CHL 可以从 PPAHC 纳米前药中快速释放。此外，通过抗增殖研究和细胞凋亡测定，PPAHC 纳米前药与 CHL 相比表现出更高的治疗效率。进一步测量肿瘤细胞中的 GSH 含量和 ROS 水平表明，QM 介导的 GSH 减少和 CHL 诱导的肿瘤细胞进一步氧化应激损伤的协同作用。体内肿瘤抑制作用和生物相容性表明 PPAHC 纳米前药具有优越性。因此，PPAHC 为 ROS 响应性 CHL 递药系统提供了一种新方法，在癌症治疗方面具有巨大潜力。
