title: Macromolecular Pt(IV) Prodrugs from Poly(organo)phosphazenes.
abstract: The preparation of novel macromolecular prodrugs via the conjugation of two platinum(IV) complexes to suitably functionalized poly(organo)phosphazenes is presented. The inorganic/organic polymers provide carriers with controlled dimensions due to the use of living cationic polymerization and allow the preparation of conjugates with excellent aqueous solubility but long-term hydrolytic degradability. The macromolecular Pt(IV) prodrugs are designed to undergo intracellular reduction and simultaneous release from the macromolecular carrier to present the active Pt(II) drug derivatives. In vitro investigations show a significantly enhanced intracellular uptake of Pt for the macromolecular prodrugs when compared to small molecule Pt complexes, which is also reflected in an increase in cytotoxicity. Interestingly, drug-resistant sublines also show a significantly smaller resistance against the conjugates compared to clinically established platinum drugs, indicating that an alternative uptake route of the Pt(IV) conjugates might also be able to overcome acquired resistance against Pt(II) drugs. In vivo studies of a selected conjugate show improved tumor shrinkage compared to the respective Pt(IV) complex.
authors.affiliation: Institute of Polymer Chemistry, Johannes Kepler University Linz, Altenberger Straße 69, 4040 Linz, Austria.
authors.forename: Helena
authors.initials: H
authors.lastname: Henke
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Kushtrim
authors.initials: K
authors.lastname: Kryeziu
authors.affiliation: Institute of Inorganic Chemistry University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Jelena
authors.initials: J
authors.lastname: Banfić
authors.affiliation: Research Platform "Translational Cancer Therapy Research," University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Sarah
authors.initials: S
authors.lastname: Theiner
authors.affiliation: Department of Environmental Geosciences, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Körner
authors.affiliation: Institute of Polymer Chemistry, Johannes Kepler University Linz, Altenberger Straße 69, 4040 Linz, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüggemann
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Research Platform "Translational Cancer Therapy Research," University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Institute of Polymer Chemistry, Johannes Kepler University Linz, Altenberger Straße 69, 4040 Linz, Austria.
authors.forename: Ian
authors.initials: I
authors.lastname: Teasdale
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010984:Platinum / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D009944:Organoplatinum Compounds; D011355:Prodrugs; D000077150:Oxaliplatin; D010984:Platinum
keywords: biodegradable; nanomedicine; platinum(IV) prodrugs; polymer therapeutics; polyphosphazenes