Synthesis and antitumor activity of novel polyphosphazene-(diamine)platinum(II) conjugates

Abstract A novel class of water-soluble polyphosphazene-(diamine)platinum(II) conjugate drugs [N=P(S)Am·PtA 2 )] n have been designed and synthesized by incorporating the antitumor (diamine)platinum(II) moiety (A 2 Pt 2+ ) to a polyphosphazene back-bone along with a solubilizing groups (S) employing dicarboxylic amino acid (Am) as a spacer group. After characterization of these polymer conjugates by means of multinuclear ( 1 H, 31 P, 195 Pt) NMR and IR spectroscopies, elemental analysis and GPC, their antitumor activity were evaluated both in vitro and in vivo against murine leukemia L1210 cell lines and in vitro against five human tumor cell lines. Most of the title polymer conjugates have shown higher in vivo antitumor activity than cisplatin, and in particular [N=P(OH)(Glu·Pt(DACH))] n (Glu=glutamate, DACH= trans (±)-1,2-diaminocyclohexane) exhibit extraordinary high activity (ILS(%)>500) without cross-resistance to cisplatin as well as good water solubility, and therefore, was subjected to preclinical studies for human clinical trials.