Cardiovascular Research Advance Access first published online on January 3, 2008
This version [Accepted Manuscript] published online on January 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm115
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Molecular imaging of 
vβ3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA
1 Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons-Hainaut, 24, Avenue du Champ de Mars, B-7000 Mons, Belgium
2 Department of Histology, University of Mons-Hainaut, 24, Avenue du Champ de Mars, B-7000 Mons, Belgium
3 Laboratory of Radiopharmacy, Department of Pharmaceutical Sciences, Catholic University of Louvain, Onderwijs en Navorsing 2, Box 821, B-3000 Leuven, Belgium
* Corresponding author: Professor Robert N. Muller, Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons-Hainaut, 24, Avenue du Champ de Mars, B-7000 Mons, Belgium. Tel/Fax: +32 - 65 - 373520, e-mail address: Robert.Muller{at}umh.ac.be
Aim: The integrin 
vβ3 is highly expressed in atherosclerotic plaques by medial and intimal smooth muscle cells and by endothelial cells of angiogenic microvessels. In this study we have assessed noninvasive molecular magnetic resonance imaging (MRI) of plaque-associated vβ3 integrin expression on transgenic ApoE–/- mice with a low molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD) grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD). The analogous compound Eu-DTPA-g-mimRGD was employed for an in vivo competition experiment and to confirm the molecular targeting. The specific interaction of mimRGD conjugated to Gd-DTPA or to 99mTc-DTPA with vβ3 integrin was furthermore confirmed on Jurkat T lymphocytes.
Methods: The mimRGD was synthesized and conjugated to DTPA. DTPA-g-mimRGD was complexed with GdCl3x6H2O, EuCl3x6H2O, or with [99mTc(CO)3(H2O)3]+. MRI evaluation was performed on a 4.7 T Bruker imaging system. Blood pharmacokinetics of Gd-DTPA-g-mimRGD were assessed in Wistar rats and in c57bl/6j mice. The presence of angiogenic blood vessels and the expression of vβ3 integrin were confirmed in aorta specimens by immunohistochemistry.
Results: Gd-DTPA-g-mimRGD produced a strong enhancement of the external structures of the aortic wall and of the more profound layers (possibly tunica media and intima). The aortic lumen seemed to be restrained and distorted. Pre-injection of Eu-DTPA-g-mimRGD diminished the Gd-DTPA-g-mimRGD binding to atherosclerotic plaque and confirmed the specific molecular targeting. A slower blood clearance was observed for Gd-DTPA-g-mimRGD, as indicated by a prolonged elimination half-life and a diminished total clearance.
Conclusions: The new compound is potentially useful for the diagnosis of vulnerable atherosclerotic plaques and of other pathologies characterized by vβ3 integrin expression, such as cancer and inflammation. The delayed blood clearance, the significant enhancement of the signal-to-noise ratio, and the low immunogenicity of the mimetic molecule highlight its potential for an industrial and clinical implementation.
KEYWORDS atherosclerosis; angiogenesis; inflammation; NMR
Time for primary review: 23 days
Note: Parts of this work have been presented at the 23rd Annual Meeting of ESMRMB Warsaw, Poland, September 22 – 28, 2006.
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