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Acidity-Biodegradable Iridium-Coordinated Nanosheets for Amplified Ferroptotic Cell Death Through Multiple Regulatory

Lili Huang1,2, Tongtong Nie1, Lixian Jiang1

  • 1Department of Ultrasound in Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, P. R. China.

Advanced Healthcare Materials
|January 7, 2023
PubMed

Insights

This study introduces novel iridium-coordinated nanosheets (Ir-Hemin) that effectively induce ferroptosis, a cell death pathway, in cancer cells. These nanosheets enhance reactive oxygen species (ROS) and iron levels, overcoming limitations in current cancer therapies.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cancer Therapy

Background:

  • Ferroptosis is a promising cancer treatment strategy for tumors resistant to apoptosis.
  • Current ferroptosis therapies face challenges due to low intracellular reactive oxygen species (ROS) and iron levels.
  • Developing effective strategies to enhance ferroptosis is crucial for clinical translation.

Purpose of the Study:

  • To develop an intracellular acid-biodegradable iridium-coordinated nanosheet (Ir-Hemin) for sonodynamic therapy (SDT).
  • To investigate the potential of Ir-Hemin nanosheets to induce ferroptosis in tumor cells via multiple regulatory pathways.
  • To evaluate the synergistic anticancer efficacy of Ir-Hemin nanosheets under ultrasound (US) stimulation.

Main Methods:

  • Synthesis of intracellular acid-biodegradable iridium-coordinated nanosheets (Ir-Hemin).
  • Utilizing Ir-Hemin nanosheets as nanosonosensitizers under ultrasound (US) irradiation to generate ROS.
  • Investigating the decomposition of Ir-Hemin to release hemin and Ir(IV), leading to glutathione (GSH) depletion and GPX4 deactivation.
  • Assessing heme oxygenase 1 (HO-1) upregulation for endogenous ferrous ion supplementation.
  • Evaluating in vitro and in vivo anticancer efficacy and tumor accumulation of Ir-Hemin nanosheets.

Main Results:

  • Ir-Hemin nanosheets effectively generate ROS under US irradiation, leading to lipid peroxide accumulation and ferroptosis.
  • Decomposition of Ir-Hemin depletes GSH, deactivates GPX4, and initiates the ferroptosis pathway.
  • Released hemin upregulates HO-1, providing endogenous ferrous ions and mitigating toxicity concerns.
  • Ir-Hemin nanosheets demonstrate high tumor accumulation and trigger effective ferroptosis.
  • Pronounced synergistic anticancer efficacy was observed both in vitro and in vivo under US stimulation.

Conclusions:

  • Ir-Hemin nanosheets represent a novel strategy for inducing ferroptosis through SDT.
  • This approach effectively overcomes limitations of insufficient ROS and iron levels in cancer therapy.
  • Ir-Hemin nanosheets show significant potential for synergistic anticancer treatment, warranting further clinical investigation.
Keywords:
cancer treatmentferroptosislipid peroxidessonodynamic therapy

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