Elucidating the underlying photochemical mechanisms of action (MoA) of photodynamic therapy (PDT) may allow its efficacy to be improved and could set the stage for the development of new classes of PDT photosensitizers. Here, we provide evidence that “photoredox catalysis in cells,” wherein key electron transport pathways are disrupted, could constitute a general MoA associated with PDT. Taking the cellular electron donor nicotinamide adenine dinucleotide as an example, we have found that well-known photosensitizers, such as Rose Bengal, BODIPY, phenoselenazinium, phthalocyanine, and porphyrin derivatives, are able to catalyze its conversion to NAD+. This MoA stands in contrast to conventional type I and type II photoactivation mechanisms involving electron and energy transfer, respectively. A newly designed molecular targeting photocatalyst (termed CatER) was designed to test the utility of this mechanism-based approach to photosensitizer development. Photoexcitation of CatER induces cell pyroptosis via the caspase 3/GSDME pathway. Specific epidermal growth factor receptor positive cancer cell recognition, high signal-to-background ratio tumor imaging (SBRTI = 12.2), and good tumor growth inhibition (TGI = 77.1%) are all hallmarks of CatER. CatER thus constitutes an effective near-infrared pyroptotic cell death photo-inducer. We believe the present results will provide the foundation for the synthesis of yet-improved phototherapeutic agents that incorporate photocatalytic chemistry into their molecular design.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2022 Aug 23|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We gratefully acknowledge financial support from the National Research Foundation of Korea (CRI project 2018R1A3B1052702 to J.S.K.), the National Natural Science Foundation of China (Project 22090011), and NSFC-Liaoning United Fund (U1908202). We also thank the Brain Pool Program administered through the National Research Foundation of Korea (NRF) (2020H1D3A1A02080172 to M.L.) for financial support. The work in Austin was supported by the Robert A. Welch Foundation (F-0018 to J.L.S.).
Copyright © 2022 the Author(s). Published by PNAS.
- photodynamic therapy
- photoredox catalysis
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