Copper-Based Metal-Organic Framework Overcomes CancerChemoresistance through Systemically Disrupting DynamicallyBalanced Cellular Redox Homeostasis

Chemodrug resistance is a major reason accountingfor tumor recurrence. Given the mechanistic complexity ofchemodrug resistance, molecular inhibitors and targeting drugsoften fail to eliminate drug-resistant cancer cells, and sometimeseven promote chemoresistance by activating alternative pathways.Here, by exploiting biochemical fragility of high-level butdynamically balanced cellular redox homeostasis in drug-resistantcancer cells, we design a nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs thishomeostasis tilting the balance toward oxidative stress. Withindrug-resistant cells, CuHPT starts disassembly that is triggered bypersistent consumption of cellular glutathione (GSH). CuHPTdisassembly simultaneously releases two structural elements:catechol ligands and reductive copper ions (Cu+). Both of them cooperatively function to amplify the production of intracellularradical oxidative species (ROS) via auto-oxidation and Fenton-like reactions through exhausting GSH. By drastically heighteningcellular 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, alongwith CuHPT's good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidencesupporting the notion that this copper-based MOF is a predesigned smart therapeutic against drug-resistant cancers throughprecisely deconstructing their redox homeostasis.

Automated summary

This study presents a copper/catechol-based metal-organic framework that disrupts the redox homeostasis in drug-resistant cancer cells, leading to increased cellular oxidative stress and selective cytotoxicity. The framework effectively inhibits in vivo drug-resistant tumor growth and improves survival rates in tumor-bearing mice.