title: A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models.
abstract: Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics.
authors.affiliation: Graduate Program in Chemistry and Chemical Biology, University of California-San Francisco , San Francisco, California 94158, United States.|Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Spangler
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Fontaine
authors.affiliation: SRI International , Menlo Park, California 94025-3493, United States.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Shi
authors.affiliation: SRI International , Menlo Park, California 94025-3493, United States.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sambucetti
authors.forename: Aras N
authors.initials: AN
authors.lastname: Mattis
authors.affiliation: Preclinical Therapeutic Core, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: Byron
authors.initials: B
authors.lastname: Hann
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.|Department of Cellular and Molecular Pharmacology, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Wells
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: Adam R
authors.identifier: 0000-0002-1240-2846
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D005260:Female; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000080890:Duocarmycins; D005296:Ferrous Compounds; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C066098:duocarmycin SA