Metal-phenolic networks specifically eliminate hypoxic tumors by instigating oxidative and proteotoxic stresses

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Hypoxia is common in solid tumors, hindering cancer treatment efficacy.
• Current clinical strategies for hypoxic tumors are limited.
• Targeting tumor hypoxia is crucial for improving cancer therapy outcomes.

Purpose of the Study:

• To develop a nanotherapeutic agent targeting and eliminating hypoxic cancer cells.
• To investigate the mechanism of action of the developed agent.
• To evaluate the therapeutic efficacy and biocompatibility of the agent in preclinical models.

Main Methods:

• Fabrication of metal-phenolic networks (CuGI) using epigallocatechin gallate and copper ions.
• Investigation of CuGI's effect on metabolic pathways in hypoxic cancer cells.
• Assessment of reactive oxygen species production and protein oligomerization.
• Evaluation of apoptosis and cuproptosis induction in hypoxic cancer cells.
• Preparation and testing of cancer cell membrane-coated CuGI (CuGI@CM) for tumor penetration and efficacy.
• Combination therapy studies with vascular disruptors and radiotherapy.

Main Results:

• CuGI effectively redirects metabolism from glycolysis to oxidative phosphorylation in hypoxic cancer cells.
• CuGI enhances reactive oxygen species production and promotes lipoylated protein oligomerization.
• CuGI selectively induces apoptosis and cuproptosis in hypoxic cancer cells, sparing normal cells.
• CuGI@CM demonstrates improved tumor penetration and suppresses colorectal tumor growth.
• CuGI@CM shows synergistic effects when combined with therapies that exacerbate tumor hypoxia.

Conclusions:

• CuGI is a potent nanotherapeutic agent specifically targeting and eliminating hypoxic tumors.
• CuGI offers a promising strategy for addressing tumor hypoxia in cancer treatment.
• CuGI holds potential for combination therapies to enhance overall cancer treatment efficacy.