Author + information
- Received February 7, 2012
- Revision received May 14, 2012
- Accepted June 29, 2012
- Published online March 1, 2013.
- Wei Chen, PhD⁎,†,
- David P. Cormode, PhD⁎,†,
- Yuliya Vengrenyuk, PhD‡,
- Beatriz Herranz, PhD⁎,§,
- Jonathan E. Feig, MD, PhD‡,
- Ahmed Klink, PhD⁎∥,
- Willem J.M. Mulder, PhD⁎,¶,
- Edward A. Fisher, MD, PhD‡,⁎⁎ ( and )
- Zahi A. Fayad, PhD⁎,†,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Zahi A. Fayad, Icahn School of Medicine at Mount Sinai, Translational and Molecular Imaging Institute, One Gustave L. Levy Place, New York, New York 10029
- ↵>⁎⁎Dr. Edward A. Fisher, New York University School of Medicine, Smilow 8, 522 First Avenue, New York, New York 10016
Objectives This study sought to develop magnetic resonance contrast agents based on high-density lipoprotein (HDL) nanoparticles to noninvasively visualize intraplaque macrophages and collagen content in mouse atherosclerotic plaques.
Background Macrophages and collagen are important intraplaque components that play central roles in plaque progression and/or regression. In a Reversa mouse model, plaque regression with compositional changes (from high macrophage, low collagen to low macrophage, high collagen) can be induced.
Methods This study labeled HDL nanoparticles with amphiphilic gadolinium chelates to enable target-specific imaging of intraplaque macrophages. To render HDL nanoparticles specific for the extracellular matrix, labeled HDL nanoparticles were functionalized with collagen-specific EP3533 peptides (EP3533-HDL) via poly(ethylene glycol) spacers embedded in the HDL lipid layers. The association of nanoparticles with collagen was examined in vitro by optical methods. The in vivo magnetic resonance efficacy of these nanoparticles was evaluated in a Reversa mouse model of atherosclerosis regression. Ex vivo confocal microscopy was applied to corroborate the in vivo findings and to evaluate the fate of the different HDL nanoparticles.
Results All nanoparticles had similar sizes (10 ± 2 nm) and longitudinal relaxivity r1 (9 ± 1 s−1 mmol/l−1). EP3533-HDL showed strong association with collagen in vitro. After 28 days of plaque regression in Reversa mice, EP3533-HDL showed significantly increased (p < 0.05) in vivo magnetic resonance signal in aortic vessel walls (normalized enhancement ratio [NERw] = 85 ± 25%; change of contrast-to-noise ratio [ΔCNRw] = 17 ± 5) compared with HDL (NERw = −7 ± 23%; ΔCNRw = −2 ± 4) and nonspecific control EP3612-HDL (NERw = 4 ± 24%; ΔCNRw = 1 ± 6) at 24 h after injection. Ex vivo confocal images revealed the colocalization of EP3533-HDL with collagen. Immunohistostaining analysis confirmed the changes of collagen and macrophage contents in the aortic vessel walls after regression.
Conclusions This study shows that the HDL nanoparticle platform can be modified to monitor in vivo plaque compositional changes in a regression environment, which will facilitate understanding plaque regression and the search for therapeutic interventions.
This work was partially support by the following grants: NIH/NHLBIR01 HL71021, NIH/NBIBR01 EB009638, and NIH/NHLBI Program of Excellence in Nanotechnology (PEN) Award, HHSN268201000045C (to Dr. Fayad) and NHLBIP01HL098055, R01HL084312 (to Dr. Fisher). CSL Ltd. donated apolipoprotein A-I. Dr. Cormode has received research support from the National Institutes of Health, grant NIH K99 EB012165. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Eike Nagel, MD, PhD, served as Guest Editor for this article.
- Received February 7, 2012.
- Revision received May 14, 2012.
- Accepted June 29, 2012.
- American College of Cardiology Foundation