Polymer/Dendrimer Supported Organoplatinum Drugs

Organoplatinum antitumor agents are broad-spectrum, very effective cancer drugs. The simplest of these, Cisplatin [cis-dichlorodiamineplatinum(II)], has long been a prominent component of cancer treatment. However, this drug and others of the class suffer from rather acute toxicity such that side effects associated with its use are significant. While forced-hydration therapy can be practiced to limit the concentration of active organoplatinum species in the extracellular fluid it is not highly effective in minimizing the side effects accompanying drug administration. Release of active platinum drug from a suitable carrier at a low rate might be a better approach to limiting the effective drug concentration to levels below that needed to induce side effects. Hydrophilic, biocompatible polymers have been used as carriers for platinum antitumor compounds. An initial approach involved the formation of noncovalent complexes of appropriate organoplatinum compounds with poly(N-vinylprrolidone). Direct platination of poly(acrylamide)s derived from 1,2-oxazine has been utilized to prepare a range of drug conjugates. However, the greatest potential for the generation of a suitable polymeric prodrug arises from the treatment of a generation 4.5 poly(amidoamine) [PAMAM] dendrimer with diaquo(1,2-diaminocyclohexane) platinum (II). A well-defined dendrimer-platinum conjugate containing forty (1,2-diaminocyclohexane)platinum(II) units coordinated to the dendrimer surface via carboxylate groups is formed. This adduct is well-behaved, water-soluble, contains a high loading of platinum units, and displays sustained release of active platinum species over a twenty-four hour period under physiological conditions.