A preliminary study of the toxicological properties of selected polymer-ferrocene conjugates

Prompted by early observations of the cytotoxic and antineoplastic properti es of certain ferrocene and ferricenium derivatives, efforts in this labora tory were focused on the synthesis of carrier-bound ferrocene compounds. Su bsequent cell culture tests carried out with selected conjugates obtained i n that program showed these polymers to be highly active antiproliferative agents. In the present project toxicological work has been performed in viv o on several ferrocene conjugates in an effort to assess their toxic effect s in experimental animals (CD-1 mice). The conjugates, all based on an alph a,beta -DL-polyaspartamide backbone structure, comprise the ferrocene drug model as a terminal on short side chains containing biofissionable amide or ester links for intracellular drug release. The polymers, dissolved in pho sphate-buffered saline, have been injected in predetermined concentrations into the vein of the mice, and the maximum tolerated dose ( MTD) levels hav e been determined, the latter referring to the highest dose levels administ ered that would allow long-term survival of the test animals. For the five conjugates tested, MTD levels range from about 3 to 30 mg Fe kg or 0.05-0.6 6 mmol Fe/kg. Compared on a molar metal-to-metal basis with similarly struc tured platinum conjugates tested previously (MTD. similar to0.14-2.66 mmol Pt/kg), these values are indicative of comparatively high toxicity of the f errocene polymers. Some implications of these findings are discussed.