title: HPMA copolymers platinates containing dicarboxylato ligands. Preparation, characterisation and in vitro and in vivo evaluation.
abstract: N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer platinates were prepared from polymeric intermediates containing Gly-Phe-Leu-Gly side chains terminating in either malonate or aspartate dicarboxylato ligands. Platinum(II) was bound by reaction of the dicarboxylato ligands with cis-[Pt(NH3)2(H2O)2]2+. The HPMA copolymer platinates obtained had a Mw of 29,000-31,000 Da and a platinum loading of approximately 10wt% (by AAS). This is close to the theoretical maximum value. The release rate of platinum species in vitro at pH 7.4 correlated with the expected stability of the 6 and 7 membered chelate rings; 14%/24 h platinum released in the case of the malonate and 68%/24 h platinum released in the case of the aspartate. Cisplatin and the aspartate conjugate displayed similar toxicity in vitro against B16F10 and COR-L23 cells while the malonate was at least 8-fold less toxic. The malonate conjugate showed significantly improved activity (T/C = 1.27-1.5) when compared with cisplatin (T/C = 1.18) that was not active when administered intravenously to treat a subcutaneous B16F10 tumour. The conjugate was at least 20-fold less toxic than cisplatin in vivo. After i.v. administration, the platinum accumulation in B16F10 tumour tissue showed a 19-fold increase in Pt AUC for the malonate conjugate when compared to cisplatin administered equi-dose at its maximum tolerated dose (MTD) (1 mg/kg).
authors.affiliation: Centre for Polymer Therapeutics, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gianasi
authors.forename: Robert G
authors.initials: RG
authors.lastname: Buckley
authors.forename: John
authors.initials: J
authors.lastname: Latigo
authors.forename: Mo
authors.initials: M
authors.lastname: Wasil
authors.forename: Ruth
authors.initials: R
authors.lastname: Duncan
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002460:Cell Line; D002850:Chromatography, Gel; D003998:Dicarboxylic Acids; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D008689:Methacrylates; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D003998:Dicarboxylic Acids; D008024:Ligands; D008689:Methacrylates; D009944:Organoplatinum Compounds; C032802:hydroxypropyl methacrylate