ABSTRACT
The integrins alpha vbeta3 and alpha vbeta5 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 alpha vbeta3 and alpha vbeta5, 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 alpha vbeta3 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 alpha vbeta3/alpha vbeta5-specific RGD pentapeptides or (2) transfected with RNAi for beta 3, but not beta 1, integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)-peptide conjugates by selective drug delivery to the tumor compartment.
Subject(s)
Neoplasms/blood supply , Neovascularization, Pathologic , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Peptides/chemistry , Peptides/pharmacology , Platinum/chemistry , Amino Acid Motifs , Animals , CD13 Antigens/metabolism , Cattle , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , Dose-Response Relationship, Drug , Endothelial Cells/cytology , Endothelial Cells/pathology , Humans , Inhibitory Concentration 50 , Integrin alphaV/metabolism , Neoplasms/pathology , Oligopeptides/analysis , Organometallic Compounds/chemical synthesisABSTRACT
Complex 1 undergoes H/D scrambling in methanol without concomitant liberation of either methane or dihydrogen (k(H)/k(D) = 0.76, 55 degrees C). The measured isotope effect was proposed to directly relate to the initial reductive coupling step in reductive elimination reactions.
