title: In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models.
abstract: 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.
  
  
  
  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.
  
  
  
  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 ((89)Zr), 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.
  
  
  
  We observed distinct pharmacokinetic profiles for the two (89)Zr-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 (89)Zr-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.
  
  
  
  (89)Zr 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 (i.e., phospholipids, apo A-I).
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Medina
authors.affiliation: Clinical Physiology, Nuclear Medicine, PET and Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Binderup
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lobatto
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Claudia
authors.initials: C
authors.lastname: Calcagno
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Luuk
authors.initials: L
authors.lastname: Giesen
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Wessel
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Julia
authors.initials: J
authors.lastname: Witjes
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Seigo
authors.initials: S
authors.lastname: Ishino
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Samantha
authors.initials: S
authors.lastname: Baxter
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sarayu
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Mootaz
authors.initials: M
authors.lastname: Eldib
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Sánchez-Gaytán
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Robson
authors.affiliation: School of Engineering & Applied Science, Yale University, New Haven, Connecticut.
authors.forename: Jason
authors.initials: J
authors.lastname: Bini
authors.affiliation: CRF Skirball Center for Innovation, The Cardiovascular Research Foundation, Orangeburg, New York.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Granada
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Fish
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Duivenvoorden
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiner
authors.affiliation: Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Valentín
authors.initials: V
authors.lastname: Fuster
authors.affiliation: Clinical Physiology, Nuclear Medicine and PET, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
authors.affiliation: Leon H. Charney Division of Cardiology and Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: willem.mulder@mssm.edu.
authors.forename: Willem J M
authors.initials: WJ
authors.lastname: Mulder
mesh_terms: D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001345:Autoradiography; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057054:Molecular Imaging / Q000379:methods*; D061848:Optical Imaging; D058226:Plaque, Atherosclerotic; D000072078:Positron Emission Tomography Computed Tomography; D011237:Predictive Value of Tests; D011817:Rabbits; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D014018:Tissue Distribution; D015040:Zirconium / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D015040:Zirconium
keywords: PET/CT; PET/MRI; atherosclerosis; high-density lipoprotein; zirconium-89