通过 Ru 催化剂在肿瘤细胞中靶向递送和生物正交激活前药的酸响应聚合物胶束。
Acid-Responsive Polymer Micelles for Targeted Delivery and Bioorthogonal Activation of Prodrug through Ru Catalyst in Tumor Cells.
发表日期：2024 Aug 27
作者：
Panpan Zhang, Leitao Zhang, Zhihao Wang, Qiuli Cheng, Wenlan Wu, Junbo Li, Gaofeng Liang, Ravin Narain
来源：
BIOMACROMOLECULES
摘要：
生物正交反应为最大限度地减少癌症化疗中的脱靶毒性提供了一种有前途的策略，但迫切需要可靠的纳米平台。在这里，我们制造了一种酸响应聚合物胶束，用于通过钌催化剂介导的生物正交反应在肿瘤细胞内特异性递送和激活前药。酸性溶酶体环境中腙键的断裂引发胶束的分解，促进细胞内 Alloc-DOX 和 Ru 催化剂的同时释放。随后，Alloc-DOX 的解笼锁过程被证明是由肿瘤细胞内高水平的谷胱甘肽诱导的。值得注意的是，正常细胞内有限的谷胱甘肽阻止了 Alloc-DOX 转化为活性 DOX，从而最大限度地减少了对正常细胞的毒性。在荷瘤小鼠中，这种纳米平台表现出增强的肿瘤抑制功效，同时最大限度地减少脱靶毒性。我们的研究为原位药物激活提供了一种创新方法，将癌症化疗的安全性和有效性结合起来。
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 Alloc-DOX and the Ru catalyst within the cells. Subsequently, the uncaging process of Alloc-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 Alloc-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 in situ drug activation that combines safety and effectiveness in cancer chemotherapy.