In Vivo Detection of Oxidation-Specific Epitopes in Atherosclerotic Lesions Using Biocompatible Manganese Molecular Magnetic Imaging Probes

被引:49
作者
Briley-Saebo, Karen C. [1 ,2 ,3 ]
Tuyen Hoang Nguyen [2 ]
Saeboe, Alexander M. [2 ]
Cho, Young-Seok [1 ,7 ]
Ryu, Sung Kee [1 ,8 ]
Volkava, Eugenia [2 ]
Dickson, Stephen [2 ]
Leibundgut, Gregor [1 ,6 ]
Weisner, Philipp [6 ]
Green, Simone [1 ]
Casanada, Florence [1 ]
Miller, Yury I. [6 ]
Shaw, Walter [9 ]
Witztum, Joseph L.
Fayad, Zahi A. [2 ,4 ,5 ]
Tsimikas, Sotirios [1 ]
机构
[1] Univ Calif San Diego, Vasc Med Program, La Jolla, CA 92093 USA
[2] Mt Sinai Sch Med, Dept Radiol, Imaging Sci Lab, New York, NY USA
[3] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY USA
[4] Mt Sinai Sch Med, Dept Cardiol, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA
[5] Mt Sinai Sch Med, Marie Josee & Henry R Kravis Cardiovasc Hlth Ctr, New York, NY USA
[6] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[7] Seoul Natl Univ, Div Cardiol, Seoul, South Korea
[8] Eulji Univ, Div Cardiol, Seoul, South Korea
[9] Avanti Polar Lipids, Alabaster, AL USA
基金
美国国家卫生研究院;
关键词
atherosclerosis; inflammation; molecular imaging; MRI; oxidation; IRON-OXIDE PARTICLES; CONTRAST AGENTS; PROTON RELAXATION; OXIDIZED PHOSPHOLIPIDS; CALCIUM INTERACTIONS; MONOCLONAL-ANTIBODY; RADIOLABELED MDA2; GADOLINIUM; TOXICITY; LIPOPROTEIN;
D O I
10.1016/j.jacc.2011.10.881
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objectives This study sought to evaluate the in vivo magnetic resonance imaging (MRI) efficacy of manganese [Mn(II)] molecular imaging probes targeted to oxidation-specific epitopes (OSE). Background OSE are critical in the initiation, progression, and destabilization of atherosclerotic plaques. Gadolinium [Gd(III)]based MRI agents can be associated with systemic toxicity. Mn is an endogenous, biocompatible, paramagnetic metal ion that has poor MR efficacy when chelated, but strong efficacy when released within cells. Methods Multimodal Mn micelles were generated to contain rhodamine for confocal microscopy and conjugated with either the murine monoclonal IgG antibody MDA2 targeted to malondialdehyde (MDA)-lysine epitopes or the human single-chain Fv antibody fragment IK17 targeted to MDA-like epitopes ("targeted micelles"). Micelle formulations were characterized in vitro and in vivo, and their MR efficacy (9.4-T) evaluated in apolipoprotein-deficient (apoE(-/-)) and low-density lipoprotein receptor negative (LDLR-/-) mice (0.05 mmol Mn/kg dose) (total of 120 mice for all experiments). In vivo competitive inhibition studies were performed to evaluate target specificity. Untargeted, MDA2-Gd, and IK17-Gd micelles (0.075 mmol Gd/kg) were included as controls. Results In vitro studies demonstrated that targeted Mn micelles accumulate in macrophages when pre-exposed to MDALDL with similar to 10x increase in longitudinal relativity. Following intravenous injection, strong MR signal enhancement was observed 48 to 72 h after administration of targeted Mn micelles, with colocalization within intraplaque macrophages. Co-injection of free MDA2 with the MDA2-Mn micelles resulted in full suppression of MR signal in the arterial wall, confirming target specificity. Similar MR efficacy was noted in apoE(-/-) and LDLR-/- mice with aortic atherosclerosis. No significant differences in MR efficacy were noted between targeted Mn and Gd micelles. Conclusions This study demonstrates that biocompatible multimodal Mn-based molecular imaging probes detect OSE within atherosclerotic plaques and may facilitate clinical translation of noninvasive imaging of human atherosclerosis. (J Am Coll Cardiol 2012;59:616-26) (C) 2012 by the American College of Cardiology Foundation
引用
收藏
页码:616 / 626
页数:11
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