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Indexed by:期刊论文

Date of Publication:2021-01-30

Journal:JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Volume:140

Issue:44

Page Number:14851-14859

ISSN No.:0002-7863

Key Words:Cell death; Diseases; Infrared devices; Tumors, Cancer cell apoptosis; Hypoxic environments; Intravenous administration; Near infrared light; Personalized medicines; Photodynamic therapy (PDT); Radical generation mechanisms; Therapeutic efficacy, Photodynamic therapy, antineoplastic agent; biotin; oxygen; superoxide, antihypoxia activity; apoptosis; Article; cancer cell; cancer inhibition; cancer tissue; cell transport; coculture; disease severity; dose response; drug activity; drug cytotoxicity; drug synthesis; human; in vitro study; in vivo study; ligand binding; neoplasm; nonhuman; patent; personalized medicine; photodynamic therapy; photoreactivity; radiation dose; rejuvenation; tumor ablation; tumor hypoxia

Abstract:Hypoxia, a quite universal feature in most solid tumors, has been considered as the "Achilles' heel" of traditional photodynamic therapy (PDT) and substantially impairs the overall therapeutic efficacy. Herein, we develop a near-infrared (NIR) light-triggered molecular superoxide radical (O-2(-center dot)) generator (ENBS-B) to surmount this intractable issue, also reveal its detailed O-2(-center dot) action mechanism underlying the antihypoxia effects, and confirm its application for in vivo targeted hypoxic solid tumor ablation. Photo mediated radical generation mechanism study shows that, even under severe hypoxic environment (2% O-2), ENBS-B can generate considerable O-2(-center dot) through type I photoreactions, and partial O-2(-center dot) is transformed to high toxic OH. through SOD mediated cascade reactions. These radicals synergistically damage the intracellular lysosomes, which subsequently trigger cancer cell apoptosis, presenting a robust hypoxic PDT potency. In vitro coculture model shows that, benefiting from biotin ligand, ENBS-B achieves 87-fold higher cellular uptake in cancer cells than normal cells, offering opportunities for personalized medicine. Following intravenous administration, ENBS-B is able to specifically target to neoplastic tissues and completely suppresses the tumor growth at a low light-dose irradiation. As such, we postulated this work will extend the options of excellent agents for clinical