Scientific Reports (Jun 2017)

Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity

  • Jamila Hedhli,
  • Andrzej Czerwinski,
  • Matthew Schuelke,
  • Agata Płoska,
  • Paweł Sowinski,
  • Lukas La Hood,
  • Spencer B. Mamer,
  • John A. Cole,
  • Paulina Czaplewska,
  • Maciej Banach,
  • Iwona T. Dobrucki,
  • Leszek Kalinowski,
  • Princess Imoukhuede,
  • Lawrence W. Dobrucki

DOI
https://doi.org/10.1038/s41598-017-03224-8
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 15

Abstract

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Abstract Cyclic peptides containing the Arg-Gly-Asp (RGD) sequence have been shown to specifically bind the angiogenesis biomarker α V β 3 integrin. We report the synthesis, chemical characterization, and biological evaluation of two novel dimeric cyclic RGD-based molecular probes for the targeted imaging of α V β 3 activity (a radiolabeled version, 64Cu-NOTA-PEG4-cRGD2, for PET imaging, and a fluorescent version, FITC-PEG4-cRGD2, for in vitro work). We investigated the performance of this probe at the receptor, cell, organ, and whole-body levels, including its use to detect diabetes associated impairment of ischemia-induced myocardial angiogenesis. Both versions of the probe were found to be stable, demonstrated fast receptor association constants, and showed high specificity for α V β 3 in HUVECs (K d ~ 35 nM). Dynamic PET-CT imaging indicated rapid blood clearance via kidney filtration, and accumulation within α V β 3-positive infarcted myocardium. 64Cu-NOTA-PEG4-cRGD2 demonstrated a favorable biodistribution, slow washout, and excellent performance with respect to the quality of the PET-CT images obtained. Importantly, the ratio of probe uptake in infarcted heart tissue compared to normal tissue was significantly higher in non-diabetic rats than in diabetic ones. Overall, our probes are promising agents for non-invasive quantitative imaging of α V β 3 expression, both in vitro and in vivo.