A novel cyanine photosensitizer for sequential dual-site GSH depletion and ROS-potentiated cancer photodynamic therapy

Li Chen; Jun Yang; Feijing Su; Zihang Liu; Shuai Huang; Jifa Zhang; Jinqi Li; Wuyu Mao

doi:10.1016/j.ejmech.2024.117165

A novel cyanine photosensitizer for sequential dual-site GSH depletion and ROS-potentiated cancer photodynamic therapy

Eur J Med Chem. 2024 Dec 12:283:117165. doi: 10.1016/j.ejmech.2024.117165. Online ahead of print.

Authors

Li Chen¹, Jun Yang², Feijing Su², Zihang Liu³, Shuai Huang³, Jifa Zhang⁴, Jinqi Li⁵, Wuyu Mao⁶

Affiliations

¹ Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China; Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital of Sichuan University, Chengdu, 610041, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
² Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital of Sichuan University, Chengdu, 610041, China.
³ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
⁴ Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
⁵ Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China. Electronic address: [email protected].
⁶ Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].

PMID: 39689415
DOI: 10.1016/j.ejmech.2024.117165

Abstract

The efficacy of photodynamic therapy (PDT) is often limited by the reductive microenvironment in tumor cells due to the high level of glutathione (GSH) and glutathione peroxidase 4 (GPX4), which maintain redox homeostasis. Therefore, designing a GSH-responsive photosensitizer that depletes intracellular GSH is a promising strategy to enhance PDT selectivity and efficacy. Herein, we present a GSH-selective sequentially responsive theranostic photosensitizer, Cy-Res. This cyanine agent targeting mitochondria effectively depletes two GSH molecules, leading to the generation of abundant ROS and exacerbating oxidative stress. Additionally, it achieves an 80-fold fluorescence enhancement upon response to GSH, enabling selective imaging of tumor cells. By mitigating GSH's impact on PDT, Cy-ResNPs achieves synergistic and efficient PDT treatment of invasive melanoma under low-power irradiation (808 nm, 80 mW/cm²). The inhibitory processes downregulate GPX4, increase apoptotic proteins like Bax, and promote mixed cell death involving both ferroptosis and apoptosis. Overall, this study offers new insights and strategies for the development of GSH-responsive theranostic agents, highlighting their potential for application in tumor diagnosis and therapy.

Keywords: Antitumor; Cyanine; GPX4; Glutathione depletion; Photodynamic therapy.