Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, PR China.
National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China; School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, PR China.
Biomaterials. 2021 Nov;278:121136. doi: 10.1016/j.biomaterials.2021.121136. Epub 2021 Sep 20.
Combination therapy using multiple drugs with time-programmed administration is promising for enhanced cancer treatment. However, it is still challenging to achieve time-programmed drug release from a single nanocarrier. Here, dual polyprodrugs of hemicyanine dye (CyNH) and doxorubicin (DOX) are developed to achieve time-programmed prodrug activation for synergistic cascade oxidation therapy and chemotherapy. The polyprodrug NP, composed of CyNH, is modified with a glutathione (GSH)-responsive disulfate group, while DOX is modified with a reactive oxygen species (ROS)-response thioketal (TK) group. Upon uptake by cancer cells overexpressing GSH, CyNH can be activated quickly and accumulate in the mitochondria to induce mitochondrial damage and ROS upregulation, thus achieving subsequent burst activation of DOX through the ROS-triggered cleavage of the TK linker. The early activation of CyNH makes the cancer cells more sensitive to subsequent DOX treatment for a synergistic effect of from oxidation therapy and chemotherapy. Therefore, the polyprodrug with time-programmed drug activation developed in this work provides a promising strategy for synergistic cancer therapy.
联合使用多种具有时间程序给药的药物的治疗方法有望增强癌症治疗效果。然而，仍然难以从单个纳米载体中实现时间程序药物释放。在这里，设计了半花菁染料（CyNH）和阿霉素（DOX）的双重前药，以实现协同级联氧化治疗和化学治疗的时间程序前药激活。由 CyNH 组成的聚前药 NP 用谷胱甘肽（GSH）响应的二硫酸盐基团进行修饰，而 DOX 用活性氧（ROS）响应的硫缩酮（TK）基团进行修饰。当被过表达 GSH 的癌细胞摄取时，CyNH 可以快速被激活并在细胞内积累在线粒体中，从而导致线粒体损伤和 ROS 上调，从而通过 ROS 触发的 TK 连接物的断裂来实现 DOX 的后续爆发激活。CyNH 的早期激活使癌细胞对随后的 DOX 治疗更敏感，从而产生氧化治疗和化学治疗的协同作用。因此，本工作中开发的具有时间程序药物激活的前药为协同癌症治疗提供了一种很有前途的策略。
