Copper-Based Metal–Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis

• Published in: Journal of the American Chemical Society Vol. 144; no. 11; pp. 4799 - 4809
• Main Authors: Liu, Jia, Yuan, Ye, Cheng, Yanni, Fu, Daan, Chen, Zhongyin, Wang, Yang, Zhang, Lifang, Yao, Chundong, Shi, Lin, Li, Mingyi, Zhou, Cheng, Zou, Meizhen, Wang, Guobin, Wang, Lin, Wang, Zheng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23.03.2022
• Subjects: animal models; Animals; autoxidation; biocompatibility; catechol; Catechols - pharmacology; Cell Line, Tumor; coordination polymers; copper; Copper - chemistry; cytotoxicity; Drug Resistance, Neoplasm; glutathione; Glutathione - metabolism; Homeostasis; ligands; Metal-Organic Frameworks - metabolism; Metal-Organic Frameworks - pharmacology; Mice; multiple drug resistance; neoplasms; Neoplasms - drug therapy; Oxidation-Reduction; oxidative stress; therapeutics
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.1c11856

Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, and sometimes even promote chemoresistance by activating alternative pathways. Here, by exploiting biochemical fragility of high-level but dynamically balanced cellular redox homeostasis in drug-resistant cancer cells, we design a nanosized copper/catechol-based metal–organic framework (CuHPT) that effectively disturbs this homeostasis tilting the balance toward oxidative stress. Within drug-resistant cells, CuHPT starts disassembly that is triggered by persistent consumption of cellular glutathione (GSH). CuHPT disassembly simultaneously releases two structural elements: catechol ligands and reductive copper ions (Cu+). Both of them cooperatively function to amplify the production of intracellular radical oxidative species (ROS) via auto-oxidation and Fenton-like reactions through exhausting GSH. By drastically heightening cellular oxidative stress, CuHPT exhibits selective and potent cytotoxicity to multiple drug-resistant cancer cells. Importantly, CuHPT effectively inhibits in vivo drug-resistant tumor growth and doubles the survival time of tumor-bearing mice. Thus, along with CuHPT’s good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidence supporting the notion that this copper-based MOF is a predesigned smart therapeutic against drug-resistant cancers through precisely deconstructing their redox homeostasis.