title: Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation.
abstract: Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.
authors.affiliation: CRC Institute for Cancer Studies, University of Birmingham School of Medicine, UK.
authors.forename: L W
authors.initials: LW
authors.lastname: Seymour
authors.forename: H
authors.initials: H
authors.lastname: Soyez
authors.forename: A
authors.initials: A
authors.lastname: De Marre
authors.forename: M A
authors.initials: MA
authors.lastname: Shoaibi
authors.forename: E H
authors.initials: EH
authors.lastname: Schacht
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004355:Drug Stability; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016685:Mitomycin / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D008937:Mitomycins; D008969:Molecular Sequence Data; D009842:Oligopeptides; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D008937:Mitomycins; D009842:Oligopeptides; D011355:Prodrugs; D016685:Mitomycin