title: Reconsidering azobenzene as a component of small-molecule hypoxia-mediated cancer drugs: A theranostic case study.
abstract: An azobenzene scaffold serves as both a fluorescence quencher and nitrogen mustard deactivator in a mitochondrial targeting unit bearing theranostic drug delivery system (DDS). The DDS exhibited a tissue selectivity for tumors with aggressive phenotypes, and the efficient in vitro and in vivo azoreduction under hypoxia conditions resulted in bright fluorescence at the tumor site as well as the in situ activation of the prodrug. In vivo therapeutic experiments demonstrated a significant reduction in tumor growth versus number of controls and ex vivo tissue analysis confirmed tissue normalization with strongly reduced angiogenic markers and suppressed cell proliferation. Mechanistic insight of the DDS's mode of action was gained by gene and protein expression experiments, aided by a proteomic analysis, revealing the circumvention of cellular drug resistance pathways as well as the normalization of Slit-Robo signaling, and the involvement of granzyme-triggered mitochondria-mediated apoptosis. Overall, the combined high sensitivity and synthetic ease as well as excellent therapeutic response suggests a revival of the azobenzene class of hypoxia activated drugs, especially applied to theranostics, is warranted.
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, South Korea.
authors.forename: Peter
authors.initials: P
authors.lastname: Verwilst
authors.affiliation: Department of Biotechnology, Laboratory of Stem Cells and Tissue Regeneration, College of Life Sciences & Bio Technology, Korea University, Seoul 136-701, South Korea.
authors.forename: Jiyou
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam 13135, South Korea.
authors.forename: Jiyeong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Seongnam 13135, South Korea.
authors.forename: Sora
authors.initials: S
authors.lastname: Mun
authors.affiliation: Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam 13135, South Korea; Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Seongnam 13135, South Korea. Electronic address: kanghg@eulji.ac.kr.
authors.forename: Hee-Gyoo
authors.initials: HG
authors.lastname: Kang
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, South Korea. Electronic address: jongskim@korea.ac.kr.
authors.forename: Jong Seung
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D001391:Azo Compounds / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence / Q000379:methods*; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D000068936:Theranostic Nanomedicine / Q000379:methods*; D016896:Treatment Outcome; D000072258:Tumor Hypoxia / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001391:Azo Compounds; D005456:Fluorescent Dyes; D053769:Nanocapsules; C009850:azobenzene
keywords: Azobenzene; Cancer; Drug targeting; Hypoxia; Theranostics