title: Dual targeting of hypoxic and acidic tumor environments with a cobalt(III) chaperone complex.
abstract: The rational design of prodrugs for selective accumulation and activation in tumor microenvironments is one of the most promising strategies for minimizing the toxicity of anticancer drugs. Manipulation of the charge of the prodrug represents a potential mechanism to selectively deliver the prodrug to the acidic tumor microenvironment. Here we present delivery of a fluorescent coumarin using a cobalt(III) chaperone to target hypoxic regions, and charged ligands for pH selectivity. Protonation or deprotonation of the complexes over a physiologically relevant pH range resulted in pH dependent accumulation of the fluorophore in colon cancer cells. Furthermore, in a spheroid solid tumor model, the anionic complexes exhibited preferential release of the fluorophore in the acidic/hypoxic region. By fine-tuning the physicochemical properties of the cobalt-chaperone moiety, we have demonstrated selective drug release in the acidic and hypoxic tumor microenvironment.
authors.affiliation: School of Chemistry, University of Sydney, 412C F11, Sydney 2006, New South Wales, Australia.
authors.forename: Natsuho
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Anna K
authors.initials: AK
authors.lastname: Renfrew
authors.forename: Byung J
authors.initials: BJ
authors.lastname: Kim
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Bryce
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Hambley
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003035:Cobalt; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005456:Fluorescent Dyes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006877:Hydroxamic Acids / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003374:Coumarins; D005456:Fluorescent Dyes; D006877:Hydroxamic Acids; D011355:Prodrugs; C552279:coumarin 343; D003035:Cobalt