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Isoaspartate-Glycine-Arginine: A New Tumor Vasculature–Targeting Motif

¹ Department of Biological and Technological Research-Department of Oncology, CIGT Program and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, ² Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, and ³ MolMed SpA, Milan, Italy

Requests for reprints: Angelo Corti, Department of Biological and Technological Research-Department of Oncology, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. Phone: 39-02-26434802; Fax: 39-02-26434786; E-mail: corti.angelo{at}hsr.it.

Key Words: isoDGR motif • NGR motif • tumor necrosis factor • _vβ₃ integrin • vascular targeting • angiogenesis • asparagine deamidation • isoaspartate.

Asparagine deamidation in peptides or in fibronectin fragments containing the asparagine-glycine-arginine sequence generates isoaspartate-glycine-arginine (isoDGR), a new vβ3 integrin-binding motif. Because vβ3 is expressed in angiogenic vessels, we hypothesized that isoDGR-containing peptides could be exploited as ligands for targeted delivery of drugs to tumor neovasculature. We found that a cyclic CisoDGRC peptide coupled to fluorescent nanoparticles (quantum dots) could bind vβ3 integrin and colocalize with anti-CD31, anti-vβ3, and anti-5β1 antibodies in human renal cell carcinoma tissue sections, indicating that this peptide could efficiently recognize endothelial cells of angiogenic vessels. Using CisoDGRC fused to tumor necrosis factor (TNF) we observed that ultralow doses (1–10 pg) of this product (called isoDGR-TNF), but not of TNF or CDGRC-TNF fusion protein, were sufficient to induce antitumor effects when administered alone or in combination with chemotherapy to tumor-bearing mice. The antitumor activity of isoDGR-TNF was efficiently inhibited by coadministration with an excess of free CisoDGRC, as expected for ligand-directed targeting mechanisms. These results suggest that isoDGR is a novel tumor vasculature–targeting motif. Peptides containing isoDGR could be exploited as ligands for targeted delivery of drugs, imaging agents, or other compounds to tumor vasculature. [Cancer Res 2008;68(17):7073–82]