Carrier-bound platinum and iron compounds with carcinostatic properties

• Published in: Polymers for advanced technologies Vol. 9; no. 10-11; pp. 786 - 793
• Main Author: Neuse, Eberhard W.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.10.1998
• Subjects: Agents; Amines; Cell culture; Chelation; Controlled drug delivery; Derivatives; ferrocene; HeLa cell line; Iron compounds; Metallorganic polymers; Platinum compounds; platinum(II) complexes; Solubility; water-soluble polymeric carriers
• ISSN: 1042-7147; 1099-1581
• DOI: 10.1002/(SICI)1099-1581(1998100)9:10/11<786::AID-PAT804>3.0.CO;2-5

The treatment of malignancies with carcinostatic drugs, per se or in combination with other modalities, has proved its value over many decades of clinical administration. However, despite much progress in drug research in recent years, complete cures by chemotherapy are still restricted to a small select number of cancers, whereas, in general, remissions remain incomplete or short lived, notably whenever metastatic lesions have developed or resistance phenomena emerged. In an effort to increase the effectiveness of chemotherapy, several new alleys of development are being pursued world‐wide, and one of these, involving the binding of monomeric anticancer drug systems to water‐soluble, biocompatible and biodegradable polymeric carriers, is the subject of this paper. Previously developed, polymer‐bound cis‐diaminedichloroplatinum(II) complexes are briefly discussed. The complex moiety is attached to the polymeric carrier in these conjugates through metal chelation by polymer‐connected ethylene–diamine segments. Promising antineoplastic activity is observed in tests against cultured HeLa carcinoma cells, with highest activity (IC50 ≃ 15 μg Pt/ml) shown by a polyarpartamide conjugate comprising the platinum complex as a side group. Monoamine‐coordinated platinum(II) complexes carrier‐bound through primary amine terminals on short side chains are synthetically accessible by aqueous‐phase platination of amine‐functionalized carrier polymers. A representative conjugate of this class shows antiproliferative activity (against HeLa cells) well in the general activity range of the cis‐diamineplatinum‐type polymers, suggesting that, in the polymer‐attached state, platinum complex structures deviating from the familiar cis‐diamineplatinum chelate pattern may well successfully compete with cisplatin‐type drug systems as cytotoxic agents. Organoiron compounds of the ferrocene type represent another drug system discussed in this paper. Ferrocene derivatives have shown highly promising activity both in vitro and in vivo, and carrier‐binding of ferrocenes is seen as an efficacious means of increasing their therapeutic effectiveness. A series of water‐soluble ferrocene conjugates are presented in which 4‐ferrocenylbutanoic acid is reversibly polymer‐bound by coupling with pendant amino groups. Activities against HeLa cells are in the same range as those of similar platinum conjugates. In view of low expected toxicities of the organoiron polymers, as compared with the platinum compounds, this finding has significant implications for broad‐based development of polymeric ferrocene conjugates. © 1998 John Wiley & Sons, Ltd.