Conjugated Platinum(IV)−Peptide Complexes for Targeting Angiogenic Tumor Vasculature

Abstract

The integrins α_vβ₃ and α_vβ₅ and the membrane-spanning surface protein aminopeptidase N (APN) are highly expressed in tumor-induced angiogenesis, making them attractive targets for therapeutic intervention. Both integrins and APN recognize a broad range of peptides containing RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) motifs, respectively. Here, we describe the design, synthesis, and characterization of a series of mono- and difunctionalized platinum(IV) complexes in which a conjugated peptide motif, containing RGD, (CRGDC)c, (RGDfK)c, or NGR, is appended as a “tumor-homing device” to target tumor endothelial cells selectively over healthy cells. Platinum(IV)−peptide complexes with nonspecific amino acids or peptide moieties were prepared as controls. Concentration–response curves of these compounds were evaluated against primary proliferating endothelial cells and tumor cell lines and compared to those of cisplatin, a well-described platinum-based chemotherapeutic agent. The Pt(IV)−RGD conjugates were highly and specifically cytotoxic to cell lines containing α_vβ₃ and α_vβ₅, approaching the activity of cisplatin. The Pt(IV)−NGR complexes were less active than Pt(IV)−RGD-containing compounds but more active than nonspecific Pt−peptide controls. Integrin α_vβ₃ mediated, at least in part, the anti-proliferative effect of a Pt(IV)−RGD conjugate, as demonstrated by a decreased inhibitory response when endothelial cells were either (1) incubated with an excess of α_vβ₃/α_vβ₅-specific RGD pentapeptides or (2) transfected with RNAi for β₃, but not β₁, integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)−peptide conjugates by selective drug delivery to the tumor compartment.