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Copper-Based Metal-Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically

Jia Liu1, Ye Yuan1,2, Yanni Cheng1

  • 1Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Journal of the American Chemical Society
|February 22, 2022
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A novel copper-based metal-organic framework (CuHPT) targets drug-resistant cancer cells by disrupting their redox homeostasis, inducing oxidative stress and selectively killing cancer cells. This approach shows significant potential in preclinical models for overcoming chemoresistance.

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Area of Science:

  • Biomedical Engineering
  • Materials Science
  • Oncology

Background:

  • Chemodrug resistance is a primary driver of cancer recurrence, often exacerbated by complex cellular mechanisms.
  • Conventional therapies frequently fail against resistant cancers, sometimes even promoting resistance through alternative pathways.

Purpose of the Study:

  • To design a novel therapeutic agent targeting the unique biochemical vulnerabilities of drug-resistant cancer cells.
  • To investigate the potential of a copper-based metal-organic framework (CuHPT) in overcoming chemodrug resistance.

Main Methods:

  • Development of a nanosized copper/catechol-based metal-organic framework (CuHPT).
  • Investigation of CuHPT's disassembly mechanism within cancer cells, triggered by glutathione (GSH).
  • Evaluation of CuHPT's ability to induce oxidative stress via ROS generation and GSH depletion.
  • Assessment of CuHPT's cytotoxicity against drug-resistant cancer cells in vitro and in vivo tumor growth inhibition.

Main Results:

  • CuHPT selectively disassembles in drug-resistant cells, releasing copper ions and catechol ligands.
  • Disassembly amplifies intracellular reactive oxygen species (ROS) production by depleting GSH, leading to oxidative stress.
  • CuHPT demonstrated potent and selective cytotoxicity against multiple drug-resistant cancer cell lines.
  • In vivo studies showed CuHPT effectively inhibited tumor growth and significantly improved survival rates in mice.

Conclusions:

  • CuHPT acts as a smart therapeutic by precisely deconstructing the redox homeostasis of drug-resistant cancer cells.
  • This novel copper-based MOF offers a promising strategy for overcoming chemoresistance and improving cancer treatment outcomes.