Receptor-binding, in vitro cytotoxicity, and in vivo distribution of transferrin-bound cis-platinum (II) of differing molar ratios

Abstract Complexes of cis -diamminedichloroplatinum(II) (cisplatin) and transferrin (Tf(Fe) 2 ) of differing molar ratios ( Pt Tf 3:1, 7:1, and 15:1 mol/mol) were prepared. Tf-receptor binding studies showed that the reactivity of Tf(Fe) 2 to Tf receptors on A431 cells was reduced as the binding ratio of Pt to Tf(Fe) 2 increased. The complexes of Pt Tf 3:1 and Pt Tf 7:1 inhibited the binding of 125 I-Tf(Fe) 2 to A431 cells with K i values of 26 nM and 73 nM, respectively, while the complex of Pt Tf 15:1 did not show any inhibitory activity. The in vitro cytotoxicity of Pt against A431 cells also reduced as the ratio of Pt to Tf(Fe) 2 increased, and IC 50 of Pt were 15 μM, 13 μM, and 44 μM, for the complex of Pt Tf 3:1, Pt Tf 7:1, and Pt Tf 15:1, respectively. The pharmacokinetic analysis showed that the Pt-elimination from blood was delayed when Pt was administered in the form of the complex, while the Pt-elimination rate became higher in proportion as the ratio of Pt to Tf(Fe) 2 increased. Thus, it was concluded that the receptor-binding activity, the cytotoxicity, and in vivo distribution of the complex could be optimized by altering the binding ratio of Pt to Tf(Fe) 2 , and the complex of Pt Tf 3:1 seemed to be most appropriate for the tumor-specific delivery of Pt.