Published Online
on June 9, 2008

A more recent version of this article appeared on June 24, 2008

This Article Full Text (PDF) All Versions of this Article: 117/25/3206    most recent CIRCULATIONAHA.107.757120v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Briley-Saebo, K. C. Articles by Fayad, Z. A. Search for Related Content PubMed PubMed Citation Articles by Briley-Saebo, K. C. Articles by Fayad, Z. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information MRI Scans Related Collections Cardiovascular imaging agents/Techniques Pathophysiology CT and MRI Lipid and lipoprotein metabolism Related Article

Submitted on November 30, 2007
Accepted on April 2, 2008

Targeted Molecular Probes for Imaging Atherosclerotic Lesions With Magnetic Resonance Using Antibodies That Recognize Oxidation-Specific Epitopes

Karen C. Briley-Saebo PhD, Peter X. Shaw PhD, Willem J.M. Mulder PhD, Seung-Hyuk Choi MD, Esad Vucic MD, Juan Gilberto S. Aguinaldo MD, Joseph L. Witztum MD, Valentin Fuster MD, PhD, Sotirios Tsimikas MD^*, and Zahi A. Fayad PhD^*

From the Imaging Science Laboratory, Department of Radiology (K.C.B.-S., W.M., E.V., J.G.S.A., Z.A.F.), and Department of Cardiology, Zena and Michael A. Weiner Cardiovascular Institute, and Marie-Josee and Henry R. Kravis Cardiovascular Health Center (V.F., Z.A.F.), Mount Sinai School of Medicine, New York, NY; Vascular Medicine Program, University of California, San Diego (P.X.S., S.-H.C., J.L.W., S.T.); and Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (S.-H.C.).

^* To whom correspondence should be addressed. E-mail: stsimikas{at}ucsd.edu or zahi.fayad{at}mssm.edu.

Background—Oxidized low-density lipoprotein plays a key role in the initiation, progression, and destabilization of atherosclerotic plaques and is present in macrophages and the lipid pool. The aim of this study was to assess the feasibility of magnetic resonance imaging of atherosclerotic lesions in mice using micelles containing gadolinium and murine (MDA2 and E06) or human (IK17) antibodies that bind unique oxidation-specific epitopes.

Methods and Results—MDA2 micelles, E06 micelles, IK17 micelles, nonspecific IgG micelles, and untargeted micelles (no antibody) were prepared and characterized with respect to pharmacokinetics and biodistribution in wild-type and atherosclerotic apolipoprotein E–deficient (apoE^-/-) mice. Magnetic resonance imaging was performed at 9.4 T over a 96-hour time interval after the administration of 0.075–mmol Gd/kg micelles. MDA2, E06, and IK17 micelles exhibited a longer plasma half-life than IgG or untargeted micelles in apoE^-/- but not wild-type mice. In apoE^-/- mice, MDA2 and IK17 micelles showed maximal arterial wall uptake at 72 hours and E06 micelles at 96 hours, manifested by 125% to 231% enhancement in magnetic resonance signal compared with adjacent muscle. Confocal microscopy revealed that MDA2, IK17, and E06 micelles accumulated within atherosclerotic lesions and specifically within macrophages. Intravenous injection of free MDA2 before imaging with MDA2 micelles resulted in significantly diminished magnetic resonance signal enhancement. IgG micelles and untargeted micelles showed minimal enhancement in apoE^-/- mice. There was no significant signal enhancement with all micelles in wild-type mice.

Conclusions—Magnetic resonance imaging with micelles containing gadolinium and oxidation-specific antibodies demonstrates specific targeting and excellent image quality of oxidation-rich atherosclerotic lesions.

Key words: antibodies • atherosclerosis • inflammation • lipoproteins • magnetic resonance imaging

Related Article:

Clinical Summaries
Circulation 2008 117: 3161-3162. [Extract] [Full Text]

This article has been cited by other articles:

				A. Maiseyeu, G. Mihai, T. Kampfrath, O. P. Simonetti, C. K. Sen, S. Roy, S. Rajagopalan, and S. Parthasarathy Gadolinium-containing phosphatidylserine liposomes for molecular imaging of atherosclerosis J. Lipid Res., November 1, 2009; 50(11): 2157 - 2163. [Abstract] [Full Text] [PDF]

				R. P. Choudhury and E. A. Fisher Molecular Imaging in Atherosclerosis, Thrombosis, and Vascular Inflammation Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 983 - 991. [Abstract] [Full Text] [PDF]

				J. H.F. Rudd, F. Hyafil, and Z. A. Fayad Inflammation Imaging in Atherosclerosis Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1009 - 1016. [Abstract] [Full Text] [PDF]

				D. Peters, M. Kastantin, V. R. Kotamraju, P. P. Karmali, K. Gujraty, M. Tirrell, and E. Ruoslahti Targeting atherosclerosis by using modular, multifunctional micelles PNAS, June 16, 2009; 106(24): 9815 - 9819. [Abstract] [Full Text] [PDF]

				A. E. Fraley, G. G. Schwartz, A. G. Olsson, S. Kinlay, M. Szarek, N. Rifai, P. Libby, P. Ganz, J. L. Witztum, S. Tsimikas, et al. Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial. J. Am. Coll. Cardiol., June 9, 2009; 53(23): 2186 - 2196. [Abstract] [Full Text] [PDF]

				M. J. Lipinski, J. C. Frias, V. Amirbekian, K. C. Briley-Saebo, V. Mani, D. Samber, A. Abbate, J. G. S. Aguinaldo, D. Massey, V. Fuster, et al. Macrophage-Specific Lipid-Based Nanoparticles Improve Cardiac Magnetic Resonance Detection and Characterization of Human Atherosclerosis. J. Am. Coll. Cardiol. Img., May 1, 2009; 2(5): 637 - 647. [Abstract] [Full Text] [PDF]

				J. Sanz, P. R. Moreno, and V. Fuster The Year in Atherothrombosis J. Am. Coll. Cardiol., April 14, 2009; 53(15): 1326 - 1337. [Full Text] [PDF]

				K. Hartvigsen, M.-Y. Chou, L. F. Hansen, P. X. Shaw, S. Tsimikas, C. J. Binder, and J. L. Witztum The role of innate immunity in atherogenesis J. Lipid Res., April 1, 2009; 50(Supplement): S388 - S393. [Abstract] [Full Text] [PDF]

				E. A. Osborn and F. A. Jaffer The year in molecular imaging. J. Am. Coll. Cardiol. Img., January 1, 2009; 2(1): 97 - 113. [Full Text] [PDF]

				M. Nahrendorf, D. E. Sosnovik, B. A. French, F. K. Swirski, F. Bengel, M. M. Sadeghi, J. R. Lindner, J. C. Wu, D. L. Kraitchman, Z. A. Fayad, et al. Multimodality Cardiovascular Molecular Imaging, Part II Circ Cardiovasc Imaging, January 1, 2009; 2(1): 56 - 70. [Full Text] [PDF]