细胞内
化学
阿霉素
细胞凋亡
癌症研究
脂质过氧化
癌细胞
细胞生物学
细胞质
药理学
生物化学
程序性细胞死亡
癌症
化疗
生物
酶
遗传学
作者
Xuan Wang,Yuanyuan Zhao,Yan Hu,Fei Yang,Youbo Zhao,Chencheng Xue,Kaiyong Cai,Menghuan Li,Zhong Luo
出处
期刊:Small
[Wiley]
日期:2021-09-23
卷期号:17 (47)
被引量:28
标识
DOI:10.1002/smll.202102269
摘要
Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe2+ (DOX-Fe2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H2 O2 production, but also increase the overall catalytic efficiency of Fe2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.
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