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  3. Regio-isomerization Optimization Strategy for Photosensitizers: Achieving Ultrahigh Type I Reactive Oxygen Species Generation to Enhance Cancer Photoimmunotherapy

Regio-isomerization Optimization Strategy for Photosensitizers: Achieving Ultrahigh Type I Reactive Oxygen Species Generation to Enhance Cancer Photoimmunotherapy

  • J Med Chem. 2025 Mar 27;68(6):6431-6449. doi: 10.1021/acs.jmedchem.4c02916.
Quan Wang 1,  Lili Yang 2,  Xiaoyu Xing 1,  Wenjie Liang 3,  Renzhi Wu 1,  Chen Xiong 1,  Meng Wu 4,  Cheng Zhong 5,  Haoke Zhang 6,  Shixuan Wang 4,  Fan Xia 1,  Xiaoding Lou 1,  Dugang Chen 3,  Jun Dai 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China.
  • 2 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430034, China.
  • 3 Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, China.
  • 4 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 5 College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China.
  • 6 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China.
PMID: 40080540 DOI: 10.1021/acs.jmedchem.4c02916
Abstract

Phototherapy, renowned for its noninvasiveness, is widely employed in tumor treatment. However, the tumor microenvironment is usually hypoxic, with insufficient Reactive Oxygen Species (ROS) production, severely limiting its application. Herein, we introduce a regio-isomerization optimization strategy and have synthesized four regio-isomeric photosensitizers featuring a donor-acceptor (D-A) configuration by tactically varying the linkage sites between D and A. Among them, TAF-3 with excellent photostability has an ultrahigh type I ROS production efficiency (4.79 times that of methylene blue) and a photothermal conversion efficiency of 41.7%. TAF-3 improves the conjugation degree; produces an appropriate intramolecular charge transfer effect, which enhances its optical properties and phototherapeutic efficiency; and promotes a stronger immune cell death effect, reducing postoperative melanoma recurrence by 60%. Overall, the optical attributes of D-A type photosensitizers can be tailored through the precision modulation of regio-isomerization, offering a promising avenue for the advancement of clinical photosensitizers suitable for phototherapy.

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