Nanoscale dendritic organoplatinum antitumor drugs

Organoplatinum compounds exhibit broad antitumor activity. Cisplatin [cis- dichlorodiammine platinum (II)] is the most prominent of this family and is currently the most prescribed cancer drug. It is widely used for the treatment of human testicular, ovarian, bladder, head and neck carcinomas. However, it is an extremely toxic compound and side effects such as nephrotoxicity and myelotoxicity are major drawbacks for its use in clinical applications. A way to combat the side effects associated with the administration of platinum drugs would be to generate a prodrug conjugate that, when present in the extracellular fluid, would slowly release active platinum species at a level below the threshold for side effects. Traditionally, linear hydrophilic polymers have been examined for potential application as carrier platforms for these drugs. The advent of dendrimers, which are highly branched macromolecules with precisely controlled nanoscale size, shape and end-group functionality, has provided an excellent opportunity to design and formulate novel multivalent time-release drug systems. For example, treatment of a generation 4.5 (carboxylate surface) poly(amidoamine) [PAMAM] dendrimer with diaquo(1,2-diaminocyclohexane) platinum(II) generates a nanoparticle with forty platinum moieties attached at the surface. This polymer-drug conjugate displays a very good release profile for the platinum species. Under physiological conditions about 80% of the platinum units are released over the first 24 hours. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)