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Preliminary toxicological studies of selected water‐soluble polymer–platinum conjugates
Author(s) -
Schechter Bilha,
Caldwell Gregg,
Meirim Maria G.,
Neuse Eberhard W.
Publication year - 2000
Publication title -
applied organometallic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.53
H-Index - 71
eISSN - 1099-0739
pISSN - 0268-2605
DOI - 10.1002/1099-0739(200011)14:11<701::aid-aoc26>3.0.co;2-2
Subject(s) - chemistry , ethylenediamine , platinum , conjugate , chelation , diamine , aqueous solution , polymer , stereochemistry , amine gas treating , polymer chemistry , organic chemistry , mathematical analysis , mathematics , catalysis
The objective of this preliminary investigation of a number of water‐soluble carrier‐bound platinum(II) complexes for potential use in cancer chemotherapy was to assess the toxicological behavior of representative platinum coordination compounds anchored to, or incorporated into, polymeric carriers via polymer‐attached amine ligands. The conjugates included linear polyaspartamides (1–4, 6, 7), each composed of a major fraction of subunits featuring side‐chain‐attached tertiary amino groups as water‐solubilizing entities, and a minor fraction of subunits comprising the anchored platinum complexes, again as side‐chain components. Whereas in 1–4 the platinum atom was polymer‐bound through a single amino group, both 6 and 7 contained polymer‐attached 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 ethylenediamine segments acting as cis ‐diamine chelating ligands for coordination to the platinum center. The compounds were injected as aqueous (phosphate‐buffered saline) solutions into the tail veins of CD‐1 mice (four to eight mice per conjugate), and the maximally tolerated dose was determined for each compound. For polyaspartamides 1–4 the dose levels ranged from about 25 mg Pt (kg body weight −1 ) (in conjugate 4) to 500 mg Pt kg −1 (in compound 1), the latter conjugate proving some 100‐fold less toxic than cisplatin (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 intrachain cis ‐diamineplatinum complex polymer (5). The polyaspartamide conjugates 6 and 7, on the other hand, both characterized by a cis ‐diamineplatinum complex 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 synthetic programs. Copyright © 2000 John Wiley & Sons, Ltd.