Rationally designed rapamycin-encapsulated ZIF-8 nanosystem for overcoming chemotherapy resistance
Rationally designed rapamycin-encapsulated ZIF-8 nanosystem for overcoming chemotherapy resistance
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合理设计的雷帕霉素封装 ZIF-8 纳米系统可克服化疗耐药性
DOI：
10.1016/j.biomaterials.2020.120308
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发表时间：
2020-11-01
期刊：
影响因子：
14
通讯作者：
Li, Ping
中科院分区：
文献类型：
--
作者：
Xu, Mengran;Hu, Yi;Li, Ping
沸石咪唑骨架-8（ZIF-8）纳米粒作为pH敏感的药物递送载体具有高载量，被广泛报道用于肿瘤治疗。然而，ZIF-8的细胞内腐蚀机制和相应的生物学效应，特别是自噬反应的报道很少。在此，合成的ZIF-8被证明可以诱导mTOR非依赖性和促死亡的自噬。有趣的是，自噬过程参与了ZIF-8的腐蚀。随后，锌离子释放和由于其在酸性隔室中的腐蚀而产生的活性氧直接负责肿瘤细胞的杀伤。此外，ZIF-8可以通过将细胞保护转换为促进多柔比星诱导的自噬而使肿瘤细胞对化疗敏感。mTOR信号通路的激活被证明限制了肿瘤化疗的效率。因此，构建了组合平台雷帕霉素包封的沸石咪唑酯框架（Rapa@ZIF-8），并证明了相对于单独的ZIF-8纳米颗粒或雷帕霉素处理更显著的化学敏化作用。最后，Rapa@ZIF-8和多柔比星的组合施用表现出突出的协同抗肿瘤作用，对小鼠的主要器官没有任何明显的毒性。总的来说，优化的纳米平台Rapa@ZIF-8提供了有意干扰mTOR通路和利用促进存活至死亡的自噬的开关进行辅助化疗的概念证明。
Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles are widely reported as a pH-sensitive drug delivery carrier with high loading capacity for tumor therapy. However, the mechanism of intracellular corrosion of ZIF-8 and the corresponding biological effects especially for autophagy response have been rarely reported. Herein, the as-synthesized ZIF-8 was demonstrated to induce mTOR independent and pro-death autophagy. Interestingly, the autophagic process participated in the corrosion of ZIF-8. Subsequently, zinc ion release and the generation of reactive oxygen species due to its corrosion in the acidic compartments were directly responsible for tumor cell killing. In addition, ZIF-8 could sensitize tumor cells to chemotherapy by switching cytoprotective to death promoting autophagy induced by doxorubicin. The mTOR signaling pathway activation was demonstrated to restrict tumor chemotherapy efficiency. Hence, a combined platform rapamycin encapsulated zeolitic imidazolate frameworks (Rapa@ZIF-8) was constructed and demonstrated a more significant chemo-sensitized effect relative to ZIF-8 nanoparticles or rapamycin treatment alone. Lastly, the combined administration of Rapa@ZIF-8 and doxorubicin exhibited an outstanding synergistic antitumor effect without any obvious toxicity to the major organs of mice. Collectively, the optimized nanoplatform, Rapa@ZIF-8, provides a proof of concept for intentionally interfering mTOR pathway and utilizing the switch of survival-to death-promoting autophagy for adjunct chemotherapy.