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Novel iridium and ruthenium complexes harness in-cell NADH/NADPH photocatalysis to overcome tumor hypoxia and drug resistance in cancer therapy, offering a new phototherapeutic strategy.

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Area of Science:

  • Coordination Chemistry
  • Photochemistry
  • Cancer Therapy

Background:

  • Photodynamic therapy (PDT) for cancer is hindered by tumor hypoxia, which inhibits reactive oxygen species (ROS) production.
  • In-cell NADH/NADPH depletion offers a promising mechanism to counteract hypoxia and enhance cancer treatment efficacy.
  • Existing phototherapeutic agents often suffer from poor light absorption and limited efficacy under hypoxic conditions.

Purpose of the Study:

  • To develop novel metal complexes for in-cell NADH/NADPH photocatalysis to address limitations in cancer phototherapy.
  • To design iridium and ruthenium complexes with enhanced light absorption and photocatalytic activity.
  • To investigate synergistic therapeutic strategies combining photocatalysis with other modalities.

Main Methods:

  • Synthesis and characterization of mitochondria-targeting iridium(III) and ruthenium(II) complexes.
  • Investigation of in-cell NADH/NADPH photocatalysis mechanisms, including photoinduced electron transfer and turnover frequency (TOF).
  • Evaluation of photocytotoxicity against cancer cells, including drug-resistant and hypoxic lines.
  • Design of heterodinuclear complexes for combined photocatalytic and chemotherapeutic effects.

Main Results:

  • Mitochondria-targeting Ir(III) complexes (Ir8, Ir10, Ir18) demonstrated efficient in-cell NADH photocatalysis with high TOF values.
  • Ir18 exhibited potent photocytotoxicity (IC50 = 3 nM) with strong visible light absorption.
  • Ru(II) complexes (Ru4, Ru6) enabled red-light and near-infrared (NIR) light-triggered photocatalysis, showing efficacy against resistant cancer cells.
  • A heterodinuclear Ir-Pt complex demonstrated synergistic photocatalytic and photoactivated chemotherapeutic activity.

Conclusions:

  • In-cell NADH/NADPH photocatalysis is a viable strategy to overcome hypoxia and drug resistance in cancer therapy.
  • Designed iridium and ruthenium complexes offer potent phototherapeutic agents with tunable light absorption properties.
  • This approach holds significant potential for developing innovative and effective anticancer phototherapies.