RECEPTOR-BINDING, IN-VITRO CYTOTOXICITY, AND IN-VIVO DISTRIBUTION OF TRANSFERRIN-BOUND CIS-PLATINUM(II) OF DIFFERING MOLAR RATIOS

Complexes of cis-diamminedichloroplatinum(II) (cisplatin) and transferrin (Tf(Fe)(2)) of differing molar ratios (Pt/Tf3:1, 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/Tf3:1 and Pt/Tf7:1 inhibited the binding of I-125-Tf(Fe)(2) to A431 cells with K-i values of 26 nM and 73 nM, respectively, while the complex of Pt/Tf15:1 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 IC50 of Pt were 15 mu M, 13 mu M, and 44 mu M, for the complex of Pt/Tf3:1, Pt/Tf7:1, and Pt/Tf15:1, 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/Tf3:1 seemed to be most appropriate for the tumor-specific delivery of Pt.