title: Collagen-specific peptide conjugated HDL nanoparticles as MRI contrast agent to evaluate compositional changes in atherosclerotic plaque regression.
abstract: OBJECTIVE
  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.
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Wei
authors: W
authors: Chen
authors: David P
authors: DP
authors: Cormode
authors: Yuliya
authors: Y
authors: Vengrenyuk
authors: Beatriz
authors: B
authors: Herranz
authors: Jonathan E
authors: JE
authors: Feig
authors: Ahmed
authors: A
authors: Klink
authors: Willem J M
authors: WJ
authors: Mulder
authors: Edward A
authors: EA
authors: Fisher
authors: Zahi A
authors: ZA
authors: Fayad
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology*; D001018:Aortic Diseases / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003287:Contrast Media; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008075:Lipoproteins, HDL; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles; D010316:Particle Size; D010446:Peptide Fragments; D058226:Plaque, Atherosclerotic; D011237:Predictive Value of Tests; D011379:Prognosis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D003094:Collagen; D003287:Contrast Media; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; C081026:CD68 protein, mouse; D000097382:CD68 Molecule