Polymeric drug carriers functionalized with pairwise arranged hydroxyl and/or carboxyl groups for platinum chelation

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-diaminedichlorplatinum(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%. (C) 2005 Wiley Periodicals, Inc.