In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models

JACC-CARDIOVASCULAR IMAGING

卷:9

Article

Perez-Medina, Carlos¹  Binderup, Tina^2,3  Lobatto, Mark E.^1,4  Tang, Jun⁵  Calcagno, Claudia¹  Giesen, Luuk¹  Wessel, Chang Ho¹  Witjes, Julia¹  Ishino, Seigo¹  Baxter, Samantha¹  Zhao, Yiming¹  Ramachandran, Sarayu¹  Eldib, Mootaz¹  Sanchez-Gaytan, Brenda L.¹  Robson, Philip M.¹  Bini, Jason⁶  Granada, Juan F.⁷  Fish, Kenneth M.⁸  Stroes, Erik S. G.⁴  Duivenvoorden, Raphael⁴  Tsimikas, Sotirios⁹  Lewis, Jason S.⁵  Reiner, Thomas⁵  Fuster, Valentin¹⁰  Kjaer, Andreas¹¹  Fisher, Edward A.^12,13  Fayad, Zahi A.¹  Mulder, Willem J. M.^1,14 

[1] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, One Gustave L Levy Pl,Box 1234, New York, NY 10029 USA

[2] Univ Copenhagen, Clin Physiol Nucl Med PET, Copenhagen, Denmark

[3] Univ Copenhagen, Cluster Mol Imaging, Copenhagen, Denmark

[4] Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands

[5] Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA

[6] Yale Univ, Sch Engn & Appl Sci, New Haven, CT USA

[7] Cardiovasc Res Fdn, CRF Skirball Ctr Innovat, Orangeburg, NY USA

[8] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA

[9] Univ Calif San Diego, Dept Med, Div Cardiovasc Dis, La Jolla, CA 92093 USA

[10] Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA

[11] Univ Copenhagen, Clin Physiol Nucl Med & PET, Copenhagen, Denmark

[12] NYU, Sch Med, Leon H Charney Div Cardiol, New York, NY USA

[13] NYU, Sch Med, Marc & Ruti Bell Program Vasc Biol, New York, NY USA

[14] Acad Med Ctr, Dept Med Biochem, Amsterdam, Netherlands

关键词: atherosclerosis;    high-density lipoprotein;    PET/CT;    PET/MRI;    zirconium-89;   

DOI  :  10.1016/j.jcmg.2016.01.020

来源: Elsevier

【 摘 要 】

OBJECTIVES The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities. BACKGROUND HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events. METHODS Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 (Zr-89), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model. RESULTS We observed distinct pharmacokinetic profiles for the two Zr-89-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both Zr-89-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes. CONCLUSIONS Zr-89 labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (C) 2016 by the American College of Cardiology Foundation.

【 授权许可】

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