HPMA copolymers platinates containing dicarboxylato ligands. Preparation, characterisation and in vitro and in vivo evaluation

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 10 wt% (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).