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    李广哲

    • 教授     博士生导师   硕士生导师
    • 性别:男
    • 毕业院校:日本东北大学
    • 学位:博士
    • 所在单位:化工学院
    • 学科:药物化学. 药物工程
    • 办公地点:大连理工大学西校区化工综合实验楼G313
    • 电子邮箱:liguangzhe@dlut.edu.cn

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    Unimolecular Photodynamic O-2-Economizer To Overcome Hypoxia Resistance in Phototherapeutics

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    论文类型:期刊论文

    发表时间:2020-03-18

    发表刊物:JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

    收录刊物:PubMed、SCIE

    卷号:142

    期号:11

    页面范围:5380-5388

    ISSN号:0002-7863

    摘要: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.