School of Materials Science and Engineering, Henan University of Science and Technology, Luoyang 471023, P. R. China.
School of Medicine, Henan University of Science & Technology, Luoyang 471023, P. R. China.
Biomacromolecules. 2024 Sep 9;25(9):5834-5846. doi: 10.1021/acs.biomac.4c00489. Epub 2024 Aug 27.
Bioorthogonal reactions present a promising strategy for minimizing off-target toxicity in cancer chemotherapy, yet a dependable nanoplatform is urgently required. Here, we have fabricated an acid-responsive polymer micelle for the specific delivery and activation of the prodrug within tumor cells through Ru catalyst-mediated bioorthogonal reactions. The decomposition of micelles, triggered by the cleavage of the hydrazone bond in the acidic lysosomal environment, facilitated the concurrent release of -DOX and the Ru catalyst within the cells. Subsequently, the uncaging process of -DOX was demonstrated to be induced by the high levels of glutathione within tumor cells. Notably, the limited glutathione inside normal cells prevented the conversion of -DOX into active DOX, thereby minimizing the toxicity toward normal cells. In tumor-bearing mice, this nanoplatform exhibited enhanced efficacy in tumor suppression while minimizing off-target toxicity. Our study provides an innovative approach for drug activation that combines safety and effectiveness in cancer chemotherapy.
生物正交反应为降低癌症化疗的脱靶毒性提供了一种很有前途的策略，但迫切需要一种可靠的纳米平台。在这里，我们通过 Ru 催化剂介导的生物正交反应，构建了一种酸响应性聚合物胶束，用于在肿瘤细胞内特异性递送电激活药物前药。在酸性溶酶体环境中腙键的断裂触发胶束的分解，促进了 -DOX 和细胞内 Ru 催化剂的同时释放。随后，实验证明，肿瘤细胞内高水平的谷胱甘肽诱导了 -DOX 的解笼过程。值得注意的是，正常细胞内有限的谷胱甘肽阻止了 -DOX 转化为活性 DOX，从而最大程度地降低了对正常细胞的毒性。在荷瘤小鼠中，该纳米平台在抑制肿瘤的同时表现出增强的疗效，同时最小化了脱靶毒性。我们的研究为药物激活提供了一种创新的方法，将癌症化疗的安全性和有效性结合在一起。
