Isoaspartate-glycine-arginine: A new tumor vasculature-targeting motif

Department of Biological and Technological Research, CIGT Program and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Cancer Research (Impact Factor: 9.28). 10/2008; 68(17):7073-82. DOI: 10.1158/0008-5472.CAN-08-1272
Source: PubMed

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.

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Available from: Angelo Corti, Jan 20, 2014
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    • "As it has been shown that the cyclic form of NGR has approximately ten-fold greater targeting efficacy than linear configurations of the same peptide sequence for targeting different tumors (Colombo et al., 2002), a cyclic NGR motif containing radiotracer might lead to high diagnostic efficiency. On the other hand, in order to create a 68 Ga-labeled c(NGR) conjugate a chelator other than DOTA with the ability to efficiently chelate trivalent gallium-ion at room temperature must be chosen, as thermal stability of a DOTA-c(NGR) conjugate might be insufficient due to decomposition of the cycle or the elevated temperature can enhance the conversion of asparagine residue into isoaspartate and aspartate resulting in isoDGR and DGR sequence (Curnis et al., 2008). "
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    • "The growth and metabasis of primary tumors rely on angiogenesis . Researchers (Curnis et al. 2008) have found that the NGR (aspartic acid-glycine-arginine) motif acts selectively on tumor vessel systems. Drugs combined with the NGR motif have a more potent anti-tumor activity and a lower toxicity. "
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    • "Using the procedure of Curnis et al. [31], with slight modifications, the homobifunctional crosslinker bis [sulfosuccinimiddyl] suberate (BS3) (Sigma) was used for the activation of DSPE-PEG 2000 -NH 2 in liposomes, which were then coupled to the amino group of the Cterminal lysine of the vasculature-specific peptides. Briefly, liposomes were incubated for 30 min at room temperature with BS3 at a final concentration of 1 mM, and then purified, from unreacted crosslinker, by a Sepharose CL-4B column equilibrated with Hepes buffered saline, pH 7.4 (Hepes buffer). "
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