自噬
PI3K/AKT/mTOR通路
阿霉素
沸石咪唑盐骨架
程序性细胞死亡
材料科学
化疗
活性氧
癌症研究
药理学
细胞凋亡
细胞生物学
化学
信号转导
生物
生物化学
金属有机骨架
吸附
有机化学
遗传学
作者
Mingxiang Xu,Yi Hu,Weiping Ding,Fenfen Li,Jun Lin,Min Wu,Jingjing Wu,Longping Wen,Bensheng Qiu,Pengfei Wei,Ping Li
出处
期刊:Biomaterials
[Elsevier]
日期:2020-11-01
卷期号:258: 120308-120308
被引量:79
标识
DOI:10.1016/j.biomaterials.2020.120308
摘要
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 ([email protected]) was constructed and demonstrated a more significant chemo-sensitized effect relative to ZIF-8 nanoparticles or rapamycin treatment alone. Lastly, the combined administration of [email protected] and doxorubicin exhibited an outstanding synergistic antitumor effect without any obvious toxicity to the major organs of mice. Collectively, the optimized nanoplatform, [email protected], provides a proof of concept for intentionally interfering mTOR pathway and utilizing the switch of survival-to death-promoting autophagy for adjunct chemotherapy.
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