Preliminary toxicological studies of selected water-soluble polymer-platinum conjugates

The objective of this preliminary investigation of a number of water-solubl e carrier-bound platinum(II) complexes for potential use in cancer chemothe rapy was to assess the toxicological behavior of representative platinum co ordination compounds anchored to, or incorporated into, polymeric carriers via polymer-attached amine ligands, The conjugates included linear polyaspa rtamides (1-4, 6, 7), each composed of a major fraction of subunits featuri ng side-chain-attached tertiary amino groups as water-solubilizing entities , and a minor fraction of subunits comprising the anchored platinum complex es, again as side-chain components. Whereas in 1-4 the platinum atom was po lymer-bound through a single amino group, both 6 and 7 contained polymer-at tached cis-diamine-chelating ligands coordinating to the metal center, Also included in this study was a linear polyamidoamine (5), which contained a poly(ethylene oxide) segment in the backbone in addition to intrachain ethy lenediamine segments acting as cis-diamine chelating ligands for coordinati on to the platinum center. The compounds were injected as aqueous (phosphat e-buffered saline) solutions into the tail veins of CD-1 mice (four to eigh t mice per conjugate), and the maximally tolerated dose was determined for each compound. For polyaspartamides 1-4 the dose levels ranged from about 2 5 mg Pt (kg body weight(-1)) (in conjugate 4) to 500 mg Pt kg(-1) (in compo und 1), the latter conjugate proving some 100-fold less toxic than cisplati n (3-4 mg Pt kg(-1)), which was included in this study for comparison. Low toxicity (tolerated dose 160 mg Pt kg(-1)) was also observed for the intrac hain cis-diamineplatinum complex polymer (5), The polyaspartamide conjugate s 6 and 7, on the other hand, both characterized by a cis-diamineplatinum c omplex system in the side chain, were toxic even below the dose level of 20 -25 mg Pt kg(-1). The preliminary findings of this study, while providing a basis for more extensive and broad-based toxicological studies, will serve to direct and optimize structural conjugate designs in forthcoming synthet ic programs. Copyright (C) 2000 John Wiley & Sons, Ltd.