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<div>Abstract<p>Asparagine deamidation in peptides or in fibronectin fragments containing the asparagine-glycine-arginine sequence generates isoaspartate-glycine-arginine (<i>iso</i>DGR), a new αvβ3 integrin-binding motif. Because αvβ3 is expressed in angiogenic vessels, we hypothesized that <i>iso</i>DGR-containing peptides could be exploited as ligands for targeted delivery of drugs to tumor neovasculature. We found that a cyclic C<i>iso</i>DGRC peptide coupled to fluorescent nanoparticles (quantum dots) could bind αvβ3 integrin and colocalize with anti-CD31, anti-αvβ3, and anti-α5β1 antibodies in human renal cell carcinoma tissue sections, indicating that this peptide could efficiently recognize endothelial cells of angiogenic vessels. Using C<i>iso</i>DGRC fused to tumor necrosis factor α (TNF) we observed that ultralow doses (1–10 pg) of this product (called <i>iso</i>DGR-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 <i>iso</i>DGR-TNF was efficiently inhibited by coadministration with an excess of free C<i>iso</i>DGRC, as expected for ligand-directed targeting mechanisms. These results suggest that <i>iso</i>DGR is a novel tumor vasculature–targeting motif. Peptides containing <i>iso</i>DGR 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]</p></div>