Unimolecular Photodynamic O2-Economizer To Overcome Hypoxia Resistance in Phototherapeutics

Mingle Li; Yujie Shao; Ji Hyeon Kim; Zhongji Pu; Xueze Zhao; Haiqiao Huang; Tao Xiong; Yao Kang; Guangzhe Li; Kun Shao; Jiangli Fan; James W. Foley; Jong Seung Kim; Xiaojun Peng

doi:10.1021/jacs.0c00734

Unimolecular Photodynamic O₂-Economizer To Overcome Hypoxia Resistance in Phototherapeutics

Mingle Li
, Yujie Shao
, Ji Hyeon Kim
, Zhongji Pu
, Xueze Zhao
, Haiqiao Huang
, Tao Xiong
, Yao Kang
, Guangzhe Li
, Kun Shao
, Jiangli Fan
, James W. Foley
, Jong Seung Kim^*
, Xiaojun Peng^*

^*Corresponding author for this work

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

342 Citations (Scopus)

Abstract

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O₂ delivery approaches, here we describe an innovative binary photodynamic O₂-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O₂^•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O₂ consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O₂ for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O₂^•- through type-I photochemistry, and the generated O₂^•- can further trigger a biocascade to reduce the PDT’s demand for O₂ in an O₂-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O₂-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.

Original language	English
Pages (from-to)	5380-5388
Number of pages	9
Journal	Journal of the American Chemical Society
Volume	142
Issue number	11
DOIs	https://doi.org/10.1021/jacs.0c00734
Publication status	Published - 2020 Mar 18

Bibliographical note

Funding Information:
We gratefully acknowledge the program of National Natural Science Foundation of China (project no. 21421005, 21576037), the NSFC-Liaoning United Fund (U1608222) for financial support, and a CRI project (no. 2018R1A3B1052702, JSK) of the National Research Foundation of Korea. We are also very grateful for the help of Prof. Jingyun Wang, Dr. Jing Xia, and Lianying Guo for technical assistance with mouse model construction.

Publisher Copyright:
Copyright © 2020 American Chemical Society.

ASJC Scopus subject areas

General Chemistry
Biochemistry
Catalysis
Colloid and Surface Chemistry

UN SDGs

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

Access to Document

10.1021/jacs.0c00734

Cite this

@article{3a560913b8d445f38ada8dc0a59ee3ca,

title = "Unimolecular Photodynamic O2-Economizer To Overcome Hypoxia Resistance in Phototherapeutics",

abstract = "Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2•- through type-I photochemistry, and the generated O2•- can further trigger a biocascade to reduce the PDT{\textquoteright}s demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.",

author = "Mingle Li and Yujie Shao and Kim, \{Ji Hyeon\} and Zhongji Pu and Xueze Zhao and Haiqiao Huang and Tao Xiong and Yao Kang and Guangzhe Li and Kun Shao and Jiangli Fan and Foley, \{James W.\} and Kim, \{Jong Seung\} and Xiaojun Peng",

note = "Funding Information: We gratefully acknowledge the program of National Natural Science Foundation of China (project no. 21421005, 21576037), the NSFC-Liaoning United Fund (U1608222) for financial support, and a CRI project (no. 2018R1A3B1052702, JSK) of the National Research Foundation of Korea. We are also very grateful for the help of Prof. Jingyun Wang, Dr. Jing Xia, and Lianying Guo for technical assistance with mouse model construction. Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = mar,

day = "18",

doi = "10.1021/jacs.0c00734",

language = "English",

volume = "142",

pages = "5380--5388",

journal = "Journal of the American Chemical Society",

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T1 - Unimolecular Photodynamic O2-Economizer To Overcome Hypoxia Resistance in Phototherapeutics

AU - Li, Mingle

AU - Shao, Yujie

AU - Kim, Ji Hyeon

AU - Pu, Zhongji

AU - Zhao, Xueze

AU - Huang, Haiqiao

AU - Xiong, Tao

AU - Kang, Yao

AU - Li, Guangzhe

AU - Shao, Kun

AU - Fan, Jiangli

AU - Foley, James W.

AU - Kim, Jong Seung

AU - Peng, Xiaojun

N1 - Funding Information: We gratefully acknowledge the program of National Natural Science Foundation of China (project no. 21421005, 21576037), the NSFC-Liaoning United Fund (U1608222) for financial support, and a CRI project (no. 2018R1A3B1052702, JSK) of the National Research Foundation of Korea. We are also very grateful for the help of Prof. Jingyun Wang, Dr. Jing Xia, and Lianying Guo for technical assistance with mouse model construction. Publisher Copyright: Copyright © 2020 American Chemical Society.

PY - 2020/3/18

Y1 - 2020/3/18

N2 - Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2•- through type-I photochemistry, and the generated O2•- can further trigger a biocascade to reduce the PDT’s demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.

AB - Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2•- through type-I photochemistry, and the generated O2•- can further trigger a biocascade to reduce the PDT’s demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.

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JO - Journal of the American Chemical Society

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