An Ethacrynic Acid-Brominated BODIPY Photosensitizer (EA-BPS) Construct Enhances the Lethality of Reactive Oxygen Species in Hypoxic Tumor-Targeted Photodynamic Therapy

Miae Won; Seyoung Koo; Hao Li; Jonathan L. Sessler; Jin Yong Lee; Amit Sharma; Jong Seung Kim

doi:10.1002/anie.202012687

An Ethacrynic Acid-Brominated BODIPY Photosensitizer (EA-BPS) Construct Enhances the Lethality of Reactive Oxygen Species in Hypoxic Tumor-Targeted Photodynamic Therapy

Miae Won, Seyoung Koo, Hao Li, Jonathan L. Sessler, Jin Yong Lee, Amit Sharma, Jong Seung Kim

Research output: Contribution to journal › Article › peer-review

88 Citations (Scopus)

Abstract

Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione-pi (GST-pi) is a key enzyme that militates against ROS-mediated apoptosis. We report herein a new construct, EA-BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST-pi inhibitor. Photoirradiation of EA-BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST-pi inhibition. Relative to BPS alone, an enhanced cell-killing effect is seen under hypoxic conditions both in vitro and in vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.

Original language	English
Pages (from-to)	3196-3204
Number of pages	9
Journal	Angewandte Chemie - International Edition
Volume	60
Issue number	6
DOIs	https://doi.org/10.1002/anie.202012687
Publication status	Published - 2021 Feb 8

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (CRI project no. 2018R1A3B1052702 and NRF-2019M3E5D1A01068998, J.S.K.) and funded by the Ministry of Education (Basic Science Research Program 2020R1A6A3A01100551, M.W. and 2020R1A6A3A01100558, S.K.). A.S. thanks the Department of Biotechnology, New Delhi, for a prestigious Ramalingaswami Fellowship 2019 (Grant No. BT/RLF/Re-entry/59/2018). The Robert A. Welch Foundation (F-0018 to J.L.S.) is also acknowledged.

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (CRI project no. 2018R1A3B1052702 and NRF‐2019M3E5D1A01068998, J.S.K.) and funded by the Ministry of Education (Basic Science Research Program 2020R1A6A3A01100551, M.W. and 2020R1A6A3A01100558, S.K.). A.S. thanks the Department of Biotechnology, New Delhi, for a prestigious Ramalingaswami Fellowship 2019 (Grant No. BT/RLF/Re‐entry/59/2018). The Robert A. Welch Foundation (F‐0018 to J.L.S.) is also acknowledged.

Publisher Copyright:
© 2020 Wiley-VCH GmbH

Keywords

BODIPY
Hypoxia
ethacrynic acid
glutathione S-transferase-pi
photodynamic therapy

ASJC Scopus subject areas

Catalysis
General Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.202012687

Cite this

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title = "An Ethacrynic Acid-Brominated BODIPY Photosensitizer (EA-BPS) Construct Enhances the Lethality of Reactive Oxygen Species in Hypoxic Tumor-Targeted Photodynamic Therapy",

abstract = "Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione-pi (GST-pi) is a key enzyme that militates against ROS-mediated apoptosis. We report herein a new construct, EA-BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST-pi inhibitor. Photoirradiation of EA-BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST-pi inhibition. Relative to BPS alone, an enhanced cell-killing effect is seen under hypoxic conditions both in vitro and in vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.",

keywords = "BODIPY, Hypoxia, ethacrynic acid, glutathione S-transferase-pi, photodynamic therapy",

author = "Miae Won and Seyoung Koo and Hao Li and Sessler, {Jonathan L.} and Lee, {Jin Yong} and Amit Sharma and Kim, {Jong Seung}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (CRI project no. 2018R1A3B1052702 and NRF-2019M3E5D1A01068998, J.S.K.) and funded by the Ministry of Education (Basic Science Research Program 2020R1A6A3A01100551, M.W. and 2020R1A6A3A01100558, S.K.). A.S. thanks the Department of Biotechnology, New Delhi, for a prestigious Ramalingaswami Fellowship 2019 (Grant No. BT/RLF/Re-entry/59/2018). The Robert A. Welch Foundation (F-0018 to J.L.S.) is also acknowledged. Funding Information: This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (CRI project no. 2018R1A3B1052702 and NRF‐2019M3E5D1A01068998, J.S.K.) and funded by the Ministry of Education (Basic Science Research Program 2020R1A6A3A01100551, M.W. and 2020R1A6A3A01100558, S.K.). A.S. thanks the Department of Biotechnology, New Delhi, for a prestigious Ramalingaswami Fellowship 2019 (Grant No. BT/RLF/Re‐entry/59/2018). The Robert A. Welch Foundation (F‐0018 to J.L.S.) is also acknowledged. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",

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AU - Koo, Seyoung

AU - Li, Hao

AU - Sessler, Jonathan L.

AU - Lee, Jin Yong

AU - Sharma, Amit

AU - Kim, Jong Seung

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N2 - Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione-pi (GST-pi) is a key enzyme that militates against ROS-mediated apoptosis. We report herein a new construct, EA-BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST-pi inhibitor. Photoirradiation of EA-BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST-pi inhibition. Relative to BPS alone, an enhanced cell-killing effect is seen under hypoxic conditions both in vitro and in vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.

AB - Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione-pi (GST-pi) is a key enzyme that militates against ROS-mediated apoptosis. We report herein a new construct, EA-BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST-pi inhibitor. Photoirradiation of EA-BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST-pi inhibition. Relative to BPS alone, an enhanced cell-killing effect is seen under hypoxic conditions both in vitro and in vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.

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KW - ethacrynic acid

KW - glutathione S-transferase-pi

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DO - 10.1002/anie.202012687

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SN - 1433-7851

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ER -

An Ethacrynic Acid-Brominated BODIPY Photosensitizer (EA-BPS) Construct Enhances the Lethality of Reactive Oxygen Species in Hypoxic Tumor-Targeted Photodynamic Therapy

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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