Synthesis and preliminary in vitro evaluation of polymeric dicarboxylato- and dihydroxylatoplatinum(II) chelates as antiproliferative agents

Despite much progress in the chemotherapy of cancerous diseases, antitumor drugs in current clinical use suffer from major pharmacological deficiencies. The platinum drug family, represented by the parent drug cisplatin, falls directly into this category of medicinal agents, with toxicity and resistance problems implicated as key factors leading to suboptimal therapeutic effectiveness. Polymer-drug conjugation, a technique involving the bioreversible drug binding to suitably designed, water-soluble carrier polymers, ranks as one of the most promising tools in advanced drug research for the enhancement of a drug's therapeutic index through modification of its pharmacokinetic pathway. The conjugate acts as a prodrug, transporting the bioactive constituent from central circulation to, and into, the transformed target cell, where it is released from the carrier for biological action. This technique is utilized here as a means to enhance the therapeutic effectiveness of selected platinum drug species. Platinum is polymer-bound (conjugated) through chelation with carrier-attached pairs of carboxyl or hydroxyl functionalities carrier-attached in 1,1- or 1,2-geometry, acting as leaving group ligands upon metal coordination. Within the carrier's structural framework, the ligand pairs are arranged either as main-chain constituents or else as side-chain functionalities. Platinum chelation with these functionalities is accomplished by treatment of the carrier in aqueous solution with trans-diaminocyclohexanediaquaplatinum(II) dinitrate (DACH-Pt), used here as the platination agent. Molar reactant ratios are chosen so as to achieve platinum incorporation in the range from about 4% to 7% by mass. Under these conditions the conjugates, purified by dialysis and isolated by freeze-drying, are found to retain solubility in water. Selected conjugates submitted to a preliminary in vitro screen show antiproliferative activities on a par with cisplatin against the (sensitive) HeLa cancer line, and up to ten times higher than cisplatin against the (multidrug-resistant) Colo 320 DM Line. Copyright (C) 2003 John Wiley Sons, Ltd.