Herceptin-platinum(II) binding complexes: novel cancer-cell-specific agents

We report a new series of Herceptin-platinum(II) binding complexes, Her-nLPt(II) (Her denotes Herceptin; L denotes diamino ligands and L=L1-L4; n=1, 5, or 10). Solution chemistry studies have shown that these complexes are stable under physiological conditions (pH 7.4 in PBS). The platinum(II) compound L1Pt(II)Cl(2) inhibits the growth of a panel of human cancer cell lines at sub-micromolar concentrations. Remarkable cancer-cell-specific cytotoxicity was observed with Her-nL1Pt(II) (n=1, 5, 10) toward Her2/neu-overexpressing cancer cells (SK-BR-3 and SK-OV-3) over normal fibroblast cells. Annexin V apoptosis assays in SK-BR-3 and low-Her2/neu-expressing MCF-7 breast cancer cells further confirmed the critical role of Herceptin with this cancer-cell-specific agent. It was also found that the L1Pt(II)Cl(2) complex is an efficient regulator of the apoptotic genes Bcl-2 in the treated SK-BR-3 cells. Also, enhanced regulatory effects were observed in Her-10L1Pt(II). Taken together, this study suggests a new approach for the development of mAb-platinum(II)-based targeting agents for the treatment of human cancers.