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Updated: Jun 13, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
High Photocytotoxicity Iridium(III) Complex Photosensitizer for Photodynamic Therapy Induces Antitumor Effect Through
Qing Zhang1, Dezhi Chen2, Xiaomeng Liu1
1School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, 211816, China.
Abstract:
The development of small molecule photosensitizers based on iridium complex is limited by the mismatch between therapeutic effect and systemic toxicity, as well as the incomplete understanding of the molecular mechanism underlying cell death induction. Herein, a small molecule iridium complex IrC with high photocytotoxicity is synthesized, with half maximal inhibitory concentration as low as 91 nm, demonstrating excellent anti-tumor, relief of splenomegaly, and negligible side effects. Starting from the factors of effective photosensitizers, the in-depth theoretical analysis on photon absorption efficiency, energy transfer level matching, and properties of the triplet excited state of IrC is conducted. This also elucidates the feasibility of generating the high singlet oxygen quantum yield. In addition, the death mechanism induced by IrC is focused, innovatively utilizing GPX4-overexpression and GPX4-knockout cells via CRISPR/Cas9 technique to comprehensively verify ferroptosis and its further molecular mechanism. The generation of ROS mediated by IrC, along with the direct inhibition of GPX4 and glutathione, synergistically increased cellular oxidative stress and the level of lipid peroxidation. This study provides an effective approach for small molecule complexes to induce GPX4-dependent ferroptosis at low-dose photodynamic therapy.
Insights
This study introduces a novel iridium complex (IrC) for photodynamic therapy, showing high anti-tumor efficacy with minimal toxicity. It effectively induces cancer cell death via ferroptosis, offering a promising therapeutic strategy.
Area of Science:
- Inorganic Chemistry
- Photochemistry
- Cancer Biology
Background:
- Iridium complexes show promise as photosensitizers but face challenges with toxicity and mechanism elucidation.
- Developing small molecule iridium complexes with high photocytotoxicity and low systemic toxicity is crucial for effective cancer therapy.
Purpose of the Study:
- To synthesize and characterize a novel small molecule iridium complex, IrC, with high photocytotoxicity.
- To investigate the molecular mechanism of cell death induced by IrC, focusing on ferroptosis.
- To evaluate the anti-tumor efficacy and safety profile of IrC in preclinical settings.
Main Methods:
- Synthesis and characterization of the iridium complex IrC.
- Theoretical analysis of photophysical properties including photon absorption, energy transfer, and triplet excited state.
- In vitro photocytotoxicity assays using cancer cell lines.
- Utilizing CRISPR/Cas9 technology to generate GPX4-overexpression and GPX4-knockout cells to verify ferroptosis.
- Assessing reactive oxygen species (ROS) generation, GPX4 inhibition, glutathione levels, and lipid peroxidation.
Main Results:
- The synthesized iridium complex IrC exhibits high photocytotoxicity with a half maximal inhibitory concentration (IC50) of 91 nm.
- IrC demonstrates significant anti-tumor effects and relief of splenomegaly with negligible side effects.
- Theoretical analysis confirmed high singlet oxygen quantum yield feasibility.
- IrC was found to induce GPX4-dependent ferroptosis by increasing oxidative stress and lipid peroxidation through ROS generation and direct inhibition of GPX4 and glutathione.
Conclusions:
- The novel iridium complex IrC is a potent photosensitizer for photodynamic therapy with excellent anti-tumor activity and a favorable safety profile.
- IrC effectively triggers cancer cell death via GPX4-dependent ferroptosis, elucidating a key molecular mechanism.
- This study presents a viable strategy for developing small molecule complexes to induce ferroptosis at low-dose photodynamic therapy.
