Cancerous diseases, together with cardiac afflictions, account for the predominant causes of death among the adult population of the Western world. The classical platinum drugs, with cisplatin as their parent, have established themselves for years as leading components in the oncologist's arsenal of antitumor agents. As with most other antineoplastic drugs, however, incisive pharmacological deficiencies, notably excessive systemic toxicity and induction of drug resistance, have severely curtailed their overall efficaciousness. With the objective of overcoming these counterproductive deficiencies, the technique of polymer-drug conjugation, representing an advanced modality of drug delivery, has been developed in recent years to high standards worldwide. In a drug conjugate, water-soluble macromolecular carrier constructs designed in compliance with stringent pharmacological specifications are covalently, yet bioreversibly, interconnected with the bioactive agent. As a macromolecule following a pharmacokinetic pathway different from that of non-polymeric compounds, the conjugate acts as a pro-drug favorably transporting the agent through the various body compartments to, and into, the target cell, where the agent is enzymatically or hydrolytically separated from the carrier for its biological action. In the authors' laboratories the conjugation strategy has been adopted as the primary tool for drug efficacy enhancement. The present paper describes a special type of platinum complex carrier-bound via dicarboxymetal chelation, synthesized from carboxyl-functionalized polyamide-type carriers by platination with trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate. In a series of in vitro tests antiproliferative activities have been determined against several human cancer cell lines. Whereas no improvements are observed in tests against a colorectal cancer, outstanding findings of the screening program include a 10-to 100-fold increase in cell-killing performance of the conjugates relative to the (non-polymeric) cisplatin standard against the HeLa adenocarcinoma, and distinctly reduced resistance factors (again, relative to cisplatin) in tests against the A2780 and A2780-cis pair of ovarian cell lines. These findings augur well for future developments of this class of platinum drugs. This article is dedicated to Professor Astruc.
Cancer chemotherapy, alone or in combination with other treatment modalities, has come to play an important part in the fight against malignancies. However, the anticancer drugs in current clinical administration, while efficacious and oftentimes curative against a select number of neoplasias, suffer from a variety of deficiencies, notably severe systemic toxicity and a tendency to elicit drug resistance. These pharmacological shortcomings are eminently in evidence with the outstanding class of platinum drugs as represented by cis-diaminedichloroplatinum(II) (cisplatin). The bioreversible binding (conjugating) of a medicinal agent to a water-soluble macromolecular carrier has been recognized as an effective expediency to curtail these deficiencies. In the present communication we describe the synthesis of a special class of polymers featuring hydroxyl and/or carboxyl functionalities designed for use in the construction of square-planar platinum complexes polymer-bound through dihydroxylato, hydroxylatocarboxylato, or dicarboxylato chelation. Accordingly, the polymer structures of this project contain pairs of hydroxyl, hydroxylcarboxyl, or carboxyl groups main chain-or side chain-attached in 1,2-geometry. The target polymers are obtained by a Michael addition type polymerization of bisacrylamide monomers with mono-or diamine comonomers in aqueous medium. Whereas in the first three polymers the hydroxyl and/or carboxyl functionalities are attached directly (1) or close (2, 3) to the backbone, the remaining polymers contain these functionalities as terminals on extended spacer segments. The water-soluble polymeric products, purified and fractionated by dialysis and isolated by freeze-drying, will be used as substrates for platinum conjugation in future work. However, their functional proneness to platinum binding is demonstrated in the present project through platination of an exemplifying carrier, providing a water-soluble conjugate with a Pt content of 13.5%.
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