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High Photocytotoxicity Iridium(III) Complex Photosensitizer for Photodynamic Therapy Induces Antitumor Effect Through GPX4-Dependent Ferroptosis
Small ( IF 13.0 ) Pub Date : 2024-09-09 , DOI: 10.1002/smll.202403165 Qing Zhang 1 , Dezhi Chen 2 , Xiaomeng Liu 1 , Zhewen Deng 2 , Jiaqi Li 2 , Senqiang Zhu 1 , Bo Ma 2 , Rui Liu 1 , Hongjun Zhu 1
Small ( IF 13.0 ) Pub Date : 2024-09-09 , DOI: 10.1002/smll.202403165 Qing Zhang 1 , Dezhi Chen 2 , Xiaomeng Liu 1 , Zhewen Deng 2 , Jiaqi Li 2 , Senqiang Zhu 1 , Bo Ma 2 , Rui Liu 1 , Hongjun Zhu 1
Affiliation
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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.
中文翻译：
用于光动力治疗的高光细胞毒性铱 (III) 复合光敏剂通过 GPX4 依赖性铁死亡诱导抗肿瘤作用
基于铱络合物的小分子光敏剂的开发受到治疗效果和全身毒性之间的不匹配以及对细胞死亡诱导分子机制的不完全理解的限制。本文合成了一种具有高光细胞毒性的小分子铱配合物IrC，半数抑制浓度低至91 nm ，具有优异的抗肿瘤、缓解脾肿大的作用，且副作用可忽略不计。从有效光敏剂的影响因素出发，对IrC的光子吸收效率、能量传递能级匹配以及三重激发态性质进行了深入的理论分析。这也阐明了产生高单线态氧量子产率的可行性。此外，重点关注IrC诱导的死亡机制，创新性地通过CRISPR/Cas9技术利用GPX4过表达和GPX4敲除细胞，全面验证铁死亡及其进一步的分子机制。 IrC 介导的 ROS 的产生，以及 GPX4 和谷胱甘肽的直接抑制，协同增加细胞氧化应激和脂质过氧化水平。这项研究为小分子复合物在低剂量光动力疗法中诱导 GPX4 依赖性铁死亡提供了一种有效的方法。
更新日期：2024-09-09
中文翻译：
用于光动力治疗的高光细胞毒性铱 (III) 复合光敏剂通过 GPX4 依赖性铁死亡诱导抗肿瘤作用
基于铱络合物的小分子光敏剂的开发受到治疗效果和全身毒性之间的不匹配以及对细胞死亡诱导分子机制的不完全理解的限制。本文合成了一种具有高光细胞毒性的小分子铱配合物IrC，半数抑制浓度低至91 nm ，具有优异的抗肿瘤、缓解脾肿大的作用，且副作用可忽略不计。从有效光敏剂的影响因素出发，对IrC的光子吸收效率、能量传递能级匹配以及三重激发态性质进行了深入的理论分析。这也阐明了产生高单线态氧量子产率的可行性。此外，重点关注IrC诱导的死亡机制，创新性地通过CRISPR/Cas9技术利用GPX4过表达和GPX4敲除细胞，全面验证铁死亡及其进一步的分子机制。 IrC 介导的 ROS 的产生，以及 GPX4 和谷胱甘肽的直接抑制，协同增加细胞氧化应激和脂质过氧化水平。这项研究为小分子复合物在低剂量光动力疗法中诱导 GPX4 依赖性铁死亡提供了一种有效的方法。
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