Improved imaging strategies and targeted molecular imaging contrast agents are needed to allow for the identification, characterization, and monitoring of atherosclerotic plaque. The main objective of the current research proposal is to develop sensitive biocompatible molecular imaging probes that are capable of identifying and monitoring atherosclerotic plaque progression by magnetic resonance imaging (MRI). Oxidation of low-density lipoprotein (oxLDL) has been identified as a critical factor in atherosclerotic plaque initiation, progression and de-stabilization. Since OxLDL is immunogenic, autoantibodies that specifically bind oxidation-specific epitopes have been isolated from mice (MDA2 and E06) and humans (IK17). We recently hypothesized that molecular imaging probes that selectively target oxidization-specific epitopes, present on oxLDL, may enable early in vivo detection of plaque prone to rupture. We have reported that oxLDL targeted gadolinium (Gd) micelles may be used for in vivo MR detection of oxidation-rich plaques in murine models of atherosclerosis. However, it was shown that there is a high degree of Gd biotransformation and retention that may limit the clinical translatability of this technology. The current proposal plans to solve these safety issues by producing nanoparticles containing biocompatible MR labels. Since the FDA has already approved the use manganese (Mn(II)) chelates and iron oxide particles for MR liver indications, we hypothesize that oxLDL targeted Mn(II) micelles and oxLDL targeted lipid coated iron oxide particles may provide clinically translatable biocompatible platforms for in vivo detection of atherosclerotic plaque.
Aim1 will focus on the synthesis, characterization, and MR efficacy of MDA2 labeled Mn(II) micelles and lipid coated iron oxide particles in atherosclerotic mice. The rationale for comparing targeted Mn(II) micelles and iron oxide particles is related to differences in the MR signal modulation and cellular metabolism/excretion associated with these two platforms. MDA2 was chosen as the targeting moiety due to availability.
In Aim 2 the pharmacokinetics, biodistribution, and MR imaging efficacy of the various oxLDL targeting moieties (MDA2, EO6, and IK17) will be tested in the mouse strain to be used in Aim 3. Since previous radiotracer studies show a correlation between antibody uptake and oxLDL deposition in the arterial vessel wall, we hypothesize that the arterial MR signal will correlate to oxLDL content (as determined by immunohistochemistry) following administration of oxLDL targeted Mn(II) micelles and/or lipid coated iron oxide particles. The optimal formulation (targeting moiety and Mn(II) or iron particle) will be chosen based upon biodistribution and the correlation of the MR signal to oxLDL deposition.
Aim 3 is designed to test the optimal formulation in murine models of atherosclerotic plaque progression. The goal of this aim is to evaluate the ability of this methodology to detect in vivo changes in arterial wall oxLDL deposition in response to dietary intervention. If successful, these MR probes may provide a powerful clinically translatable platform for the detection and monitoring of vulnerable atherosclerotic plaque.

Public Health Relevance

Cardiovascular disease remains the primary cause of mortality in the United States with myocardial and cerebral infarction caused by atherosclerosis accounting for these deaths. With better understanding of molecular pathways of numerous cardiovascular diseases, the latest research has focused on cellular and molecular mechanism of the disease, more particularly to high resolution non-invasive in vivo molecular imaging. The combination of targeted molecule- specific contrast agents and the capabilities of magnetic resonance imaging (MRI) can bring optimal results in early plaque detection, understand the molecular mechanism of the disease and monitor response to treatment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MEDI-A (09))
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Danthi, Narasimhan
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Nguyen, Tuyen H; Bryant, Henry; Shapsa, Ari et al. (2015) Manganese G8 dendrimers targeted to oxidation-specific epitopes: in vivo MR imaging of atherosclerosis. J Magn Reson Imaging 41:797-805
Briley-Saebo, Karen C; Nguyen, Tuyen Hoang; Saeboe, Alexander M et al. (2012) In vivo detection of oxidation-specific epitopes in atherosclerotic lesions using biocompatible manganese molecular magnetic imaging probes. J Am Coll Cardiol 59:616-26
Briley-Saebo, Karen C; Cho, Young Seok; Shaw, Peter X et al. (2011) Targeted iron oxide particles for in vivo magnetic resonance detection of atherosclerotic lesions with antibodies directed to oxidation-specific epitopes. J Am Coll Cardiol 57:337-47