Dendrimer-platinate: a novel approach to cancer chemotherapy.

A polyamidoamine (PAMAM) dendrimer generation 3.5 with a sodium carboxylate surface was conjugated to cisplatin giving a dendrimer-platinate (dendrimer-Pt; 20-25 wt% platinum) which was highly water soluble and released platinum slowly in vitro. In vivo the dendrimer-Pt and cisplatin were equi-active i.p. against i.p. L1210, and at high dose dendrimer-Pt given i.p. showed activity against i.p. B16F10 whereas cisplatin did not. Additionally, when administered i.v. to treat a palpable s.c. B16F10 melanoma, the dendrimer-Pt displayed antitumor activity whereas cisplatin was inactive. Measurement of platinum levels in blood and tissues after i.v. injection of cisplatin (1 mg/kg) or dendrimer-Pt (15 mg/kg)-the maximum tolerated dose (MTD) of these compounds-showed selective accumulation of the dendrimer-Pt in solid tumor tissue by the EPR effect (a 50-fold increase in area under curve compared with cisplatin). The dendrimer-Pt was also less toxic (3- to 15-fold) than cisplatin and thus has potential for further investigation as a novel antitumor approach.