Atherosclerosis and Matrix Metalloproteinases : Experimental Molecular MR Imaging in Vivo

• Published in: Radiology Vol. 251; no. 2; pp. 429 - 438
• Main Authors: AMIRBEKIAN, Vardan, AGUINALDO, Juan Gilberto S, FISHER, Edward A, GALIS, Zorina S, FAYAD, Zahi A, AMIRBEKIAN, Smbat, HYAFIL, Fabien, VUCIC, Esad, SIROL, Marc, WEINREB, David B, LE GRENEUR, Soizic, LANCELOT, Eric, COROT, Claire
• Format: Journal Article
• Language: English
• Published: Oak Brook, IL Radiological Society of North America 01.05.2009
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Atherosclerosis - diagnosis; Atherosclerosis - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chelating Agents - pharmacokinetics; Gadolinium - pharmacokinetics; Image Interpretation, Computer-Assisted - methods; Investigative techniques, diagnostic techniques (general aspects); Magnetic Resonance Imaging - methods; Matrix Metalloproteinases - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Imaging; Molecular Probe Techniques; Protein Interaction Mapping - methods; Reproducibility of Results; Sensitivity and Specificity; Vascular disease; Molecular imaging; In vivo; Nuclear medicine; Atherosclerosis; Radiology; Medical imagery; Cardiovascular disease; Metalloproteinase; Nuclear magnetic resonance imaging; Functional imaging
• ISSN: 0033-8419; 1527-1315
• DOI: 10.1148/radiol.2511080539

To evaluate the capability of P947, a magnetic resonance (MR) imaging contrast agent that molecularly targets matrix metalloproteinases (MMPs), to aid detection and imaging of MMPs in atherosclerotic lesions in vivo; its specificity compared with that of P1135; expression and distribution of MMPs in atherosclerotic vessels; and in vivo distribution and molecular localization of fluorescent europium (Eu) P947. The Animal Care and Use Committee approved all experiments. P947 was synthesized by attaching a gadolinium chelate (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) to a peptide that specifically binds MMPs. Scrambled form of P947 (P1135) was synthesized by replacing the targeting moiety of P947 with a scrambled peptide lacking the ability to bind MMPs. P947, P1135, and gadoterate meglumine were injected into atherosclerotic apolipoprotein E-deficient and wild-type mice. The aortic MR imaging enhancement produced by the contrast agents was measured at different times and was compared by using one-way analysis of variance. MMP expression was investigated in the aortas by using MMP immunostaining and in situ MMP zymography. A fluorescent form of P947 (Eu-P947) was synthesized to compare the in vivo distribution of the contrast agent (Eu-P947) with specific MMP immunofluorescent staining. MMP-targeted P947 facilitated a 93% increase (P < .001) in MR image signal intensity (contrast-to-noise ratio [CNR], 17.7 compared with 7.7; P < .001) of atherosclerotic lesions in vivo. Nontargeted P1135 (scrambled P947) provided 33% MR image enhancement (CNR, 10.8), whereas gadoterate meglumine provided 5% (CNR, 6.9). Confocal laser scanning microscopy demonstrated colocalization between fluorescent Eu-P947 and MMPs in atherosclerotic plaques. Eu-P947 was particularly present in the fibrous cap region of plaques. P947 improved MR imaging for atherosclerosis through MMP-specific targeting. The results were validated and provide support for further assessment of P947 as a potential tool for the identification of unstable atherosclerosis.