Robust Dual Enzyme Cascade‐Catalytic Cholesterol Depletion for Reverse Tumor Multidrug Resistance

多重耐药 阿霉素 化学 药理学 体内 癌细胞 葡萄糖氧化酶 癌症研究 生物化学 癌症 生物 抗生素 化疗 遗传学 生物技术
作者
Jing Guo,Xiaoming Du,Jiazhu Huang,Chenxin Liu,Yingying Zhou,Ying Liu,Bin Du
出处
期刊:Advanced Healthcare Materials [Wiley]
卷期号:11 (19) 被引量:8
标识
DOI:10.1002/adhm.202200859
摘要

Although combination drugs and P-glycoprotein inhibitors are the main methods to solve multidrug resistance, these methods ignore the pathological structure of drug-resistant cells and extremely limit curative effect. Herein, a new paradigm of reversing multidrug resistance with abnormal expression of cholesterol as the target is proposed, which uses the cascade catalysis of "natural enzyme" cholesterol oxidase (COD) and "nanoenzyme" Cu2+ -modified zirconium-based metal-organic framework (ZrMOF(Cu)) to convert cholesterol into the highly cytotoxic hydroxyl radicals. The doxorubicin (DOX)-loaded nanoparticles (DOX@COD-MOF) can significantly reduce the cholesterol content of cancer cells via COD, which decrease the rigidity of drug resistant cancer cell membranes and restore the sensitivity of multidrug-resistant cells to DOX. Afterward, DOX@COD-MOF is encapsulated by cancer cell membranes (CCM) to construct a bionic "dual enzyme catalytic cascade nanoreactor" (DOX@COD-MOF@CCM). Such a rational design presents a preferential accumulation tendency to tumor sites due to the homologous targeting mechanism of CCM, and affords 94.4% in tumor growth suppression without systemic toxicity in vivo. This work aims to achieve the therapeutic purpose of high efficiency and low toxicity. It has the characteristics of "converting enemy into friend, " and opens up a promising way for effectively reversing multidrug resistance of tumors.
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