Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 142, Issue 11, Pages 5380-5388Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c00734
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Funding
- National Natural Science Foundation of China [21421005, 21576037]
- NSFC-Liaoning United Fund [U1608222]
- CRI project of the National Research Foundation of Korea [2018R1A3B1052702]
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Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O-2 delivery approaches, here we describe an innovative binary photodynamic O-2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O-2(center dot-)) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O-2 consumption and down-regulate HIF-1 alpha expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O-2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O-2(center dot-) through type-I photochemistry, and the generated O-2(center dot-) can further trigger a biocascade to reduce the PDT's demand for O-2 in an O-2-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 O-2-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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