TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85081658833&partnerID=8YFLogxK
U2 - 10.1021/jacs.0c00734
DO - 10.1021/jacs.0c00734
M3 - Article
C2 - 32105455
AN - SCOPUS:85081658833
SN - 0002-7863
VL - 142
SP - 5380
EP - 5388
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 11
ER -
