Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature
| Autor: | Sumitra Mukhopadhyay, Stephen J. Lippard, Sarah M. Short, Ariel Haskel, Katie R. Barnes, Carmen M. Barnes |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Angiogenesis
Integrin Amino Acid Motifs Biomedical Engineering Pharmaceutical Science Bioengineering Peptide CD13 Antigens Article Inhibitory Concentration 50 Cell Line Tumor Neoplasms medicine Organometallic Compounds Animals Humans Cell Proliferation Platinum Pharmacology Cisplatin chemistry.chemical_classification biology Dose-Response Relationship Drug Neovascularization Pathologic Chemistry Organic Chemistry Endothelial Cells Transfection Integrin alphaV Molecular biology Amino acid Biochemistry Cell culture Drug delivery biology.protein Cattle Peptides Oligopeptides Biotechnology medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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