Water-Soluble Macromolecular Platinum Conjugates Derived from 1,2-Dihydroxyl-Functionalized Carrier Polymers

Abstract

The class of platinum-containing bioactive agents, including cisplatin as the prototype, and structurally related second- and third-generation compounds, has developed during the past two decades as one of the most important family of antitumor drugs. However, despite a highly valued general antineoplastic performance profile, their unrestricted oncological administration continues to be hampered by pharmacological shortcomings, notably excessive toxicity and induction of drug resistance. This has prompted ongoing intensive development activities in pharmaceutic laboratories worldwide, and one of the most promising approaches emanating from these activities involves the drug conjugation to biomedically functional, water-soluble carrier polymers. Such macromolecular conjugates, judiciously designed and synthesized, provide significant pharmacological advantages over non-polymeric drug systems, notably increased cell specificity and facilitated cell entry, paired with reduced toxicity and resistance problems. In the present project, this technology has been applied specifically to the synthesis of Pt-containing polymers in which the metal is carrier-bound via dihydroxylatoplatinum chelation. In the cancerous target cell, such conjugates will deliver the free bioactive Pt complex hydrolytically for its cytotoxic action. The water-soluble polymeric products, fractionated by dialysis in membrane tubing with molecular-mass cut-off of 25,000, will be submitted to an outside institution for in vitro evaluation of cytotoxic properties.