title: Isoaspartate-glycine-arginine: a new tumor vasculature-targeting motif.
abstract: Asparagine deamidation in peptides or in fibronectin fragments containing the asparagine-glycine-arginine sequence generates isoaspartate-glycine-arginine (isoDGR), a new alphavbeta3 integrin-binding motif. Because alphavbeta3 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 alphavbeta3 integrin and colocalize with anti-CD31, anti-alphavbeta3, and anti-alpha5beta1 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 alpha (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.
authors.affiliation: Department of Biological and Technological Research, CIGT Program and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Angelina
authors.initials: A
authors.lastname: Sacchi
authors.forename: Anna
authors.initials: A
authors.lastname: Gasparri
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
authors.forename: Gian-Paolo
authors.initials: GP
authors.lastname: Rizzardi
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti