Self-Amplifying Redox Dyshomeostasis: An All-Active Fenton/Diselenium-Based Nanocomposite for Multimechanistic Cancer...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Redox modulation, including ROS generation and GSH depletion, shows promise for cancer therapy.
• Clinical application of Fenton catalysts is limited by low H2O2 levels and high ROS inducer doses.
• GSH-depleting agents face challenges with dose-dependent efficacy and toxicity.

Purpose of the Study:

• To design an Fe-Se synergistic nanocomposite (NSe-GFe) to disrupt tumor redox homeostasis.
• To address limitations of existing Fenton catalysts and GSH-depleting agents.
• To evaluate the anticancer efficacy and biosafety of the NSe-GFe system.

Main Methods:

• Fabrication of NSe-GFe via thin-film hydration, combining mPEG-b-P(MSeSe-co-TMC) (PSe) and GA-Fe(II) (GFe).
• Assessment of simultaneous ROS production and GSH depletion by NSe-GFe.
• In vitro evaluation of ferroptosis and apoptosis induction in Hep3b cells.
• In vivo assessment of tumor angiogenesis inhibition via VEGFA downregulation.

Main Results:

• NSe-GFe effectively induces toxic hydroxyl radical (•OH) production and significant GSH depletion.
• The 'seesaw strategy' in NSe-GFe overcomes H2O2 limitations and mitigates NSe side-effects.
• NSe-GFe demonstrated potent ferroptosis and apoptosis induction in Hep3b cells.
• In vivo studies showed inhibited tumor angiogenesis by downregulating VEGFA, ensuring biosafety and tumor suppression.

Conclusions:

• The Fe-Se synergistic nanocomposite (NSe-GFe) offers a multi-pathway approach for cancer treatment.
• NSe-GFe effectively disrupts tumor redox balance, leading to cancer cell death.
• This composite nanoparticle shows significant potential for in vivo tumor suppression with good biosafety.