Synthesis and cytotoxic activity of dextran-immobilizing platinum(II) complex through chelate-type coordination bond

cis-Dichloro(cyclohexane-trans-l-1,2-diamine)platinum(II):Dach-Pt(chlorato) is a platinum complex which is expected to exhibit higher antitumor activity than cisplatin and which shows no cross-resistance with cisplatin. However, its strong side-effects and low water solubility have been noted. We have reported that polymer/antitumor drug conjugates show reduced side-effects and high antitumor activity. In order to provide a macromolecular prodrug of Dach-Pt having reduced side-effects and high water solubility, we synthesized dextran derivatives containing dicarboxylic acid groups to immobilize Dach-Pt via a chelate-type co ordination bo nd, dicarboxymethyl-dextran(DCM-Dex)/Dach-Pt conjugate. We investigated the release behavior of the platinum complex from the carrier polymer and the cytotoxic activity of the conjugate against p388D(1) lymphocytic leukemia cells in vitro compared with the carboxymethyl-dextran (CM-Dex)/Dach-Pt conjugate. The DCM-Dex/Dach-Pt conjugate showed almost the same level of cytotoxic activity as free Dach-Pt(chlorato) or Dach-Pt(malonato). Although the cytotoxic activity of free Dach-Pt(chlorato) was decreased by incubation in a medium with serum, the DCM-dextran/Dach-Pt conjugate kept its higher level of cytotoxic activity after incubation in a medium with serum. These results suggested that the stability of the Dach-Pt moiety in the medium was increased and cytotoxic activity of Dach-Pt was not decreased by fixation to dextran through a chelate-type coordination bond.