In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models

Carlos Pérez-Medina, Tina Binderup, Mark E. Lobatto, Jun Tang, Claudia Calcagno, Luuk Giesen, Chang Ho Wessel, Julia Witjes, Seigo Ishino, Samantha Baxter, Yiming Zhao, Sarayu Ramachandran, Mootaz Eldib, Brenda L. Sánchez-Gaytán, Philip M. Robson, Jason Bini, Juan F. Granada, Kenneth M. Fish, Erik S.G. Stroes, Raphaël DuivenvoordenSotirios Tsimikas, Jason S. Lewis, Thomas Reiner, Valentín Fuster, Andreas Kjær, Edward A. Fisher, Zahi A. Fayad, Willem J.M. Mulder

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

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 (89Zr), 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 89Zr-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 89Zr-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 89Zr 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).

Original languageEnglish
Pages (from-to)950-961
Number of pages12
JournalJACC: Cardiovascular Imaging
Volume9
Issue number8
DOIs
StatePublished - 1 Aug 2016

Keywords

  • PET/CT
  • PET/MRI
  • atherosclerosis
  • high-density lipoprotein
  • zirconium-89

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