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A mitochondria-targeted AIE photosensitizer for enhancing specificity and efficacy of ferroptosis inducer

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Abstract

Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation and lethal reactive oxygen species (ROS). To date, misregulated ferroptosis has been implicated in several types of cancers, and ferroptosis inducers can be used to promote ferroptosis in tumor cells and play an anti-tumor role. However, the specificity and efficacy of ferroptosis inducers remain unsatisfactory. Here, a new mitochondria-targeted photosensitizer (PS) with aggregation-induced emission (AIE) characteristic named TCSVP was designed, which efficiently generates ROS in mitochondria after light exposure. TCSVP administration significantly sensitizes tumor cells to ferroptosis inducer (RSL3)-mediated cell death by specifically and light-dependently triggering a moderate ROS generation in vitro and in vivo. Mechanically, the expression levels of ferroptosis related proteins Acyl-CoA synthetase long-chain family member 4 (FACL4/ACSL4) and cyclooxygenase-2 (COX2) were increased in TCSVP/RSL3-treated cells after light exposure, coupled with decreased Glutathione peroxidase 4 (GPX4) activity and excessive malondialdehyde (MDA) accumulation. This study declared that light-induced moderate ROS generation within mitochondria in cancer cells by AIE-PS can be used to enhance the specificity and efficacy of ferroptosis inducers, bringing a new synergistic strategy for tumor intervention.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81790633, 61922047, 81830054, 81902412, 81903184, 81988101, 91859205, 21788102, 51620105009), the Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-07-E00065, 21XD1404600), the Research Grants Council of Hong Kong (16306620, NHKUST609/19 and C6014-20W), and the Innovation and Technology Commission (ITC-CNERC14SC01, ITCPD/17-9, MHP/047/19 and ITS/301/18FX). We thank the support of Shanghai Key Laboratory of Hepato-biliary Tumor Biology and Military Key Laboratory on Signal Transduction. This study was also supported by the Innovation Program of Shanghai Municipal Education Commission.

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Authors and Affiliations

  1. Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Shan Wang, Hongyang Wang & Lei Chen

  2. Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Institute for Advanced Study, State Key Laboratory of Molecular Nanoscience, Division of Life Science, and Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, 999077, China

    Chao Chen, Jianyu Zhang, Jacky W. Y. Lam & Ben Zhong Tang

  3. Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200433, China

    Jianmin Wu

  4. The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China

    Hongyang Wang & Lei Chen

  5. National Center for Liver Cancer, Shanghai, 200441, China

    Hongyang Wang & Lei Chen

  6. Shenzhen Institute of Aggregate Science and Technology, School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, 518172, China

    Ben Zhong Tang

  7. AIE Institute, Guangzhou Development District, Guangzhou, 510530, China

    Ben Zhong Tang

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  1. Shan Wang
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  2. Chao Chen
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  3. Jianmin Wu
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  6. Hongyang Wang
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  7. Lei Chen
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  8. Ben Zhong Tang
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Corresponding authors

Correspondence to Hongyang Wang, Lei Chen or Ben Zhong Tang.

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Conflict of interest The authors declare no conflict of interest.

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Supporting information The supporting information is available online at http://chem.scichina.com and http://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Wang, S., Chen, C., Wu, J. et al. A mitochondria-targeted AIE photosensitizer for enhancing specificity and efficacy of ferroptosis inducer. Sci. China Chem. 65, 870–876 (2022). https://doi.org/10.1007/s11426-021-1207-0

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  • DOI: https://doi.org/10.1007/s11426-021-1207-0

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