title: PET/CT Imaging of Chemokine Receptors in Inflammatory Atherosclerosis Using Targeted Nanoparticles.
abstract: Atherosclerosis is inherently an inflammatory process that is strongly affected by the chemokine-chemokine receptor axes regulating the trafficking of inflammatory cells at all stages of the disease. Of the chemokine receptor family, some specifically upregulated on macrophages play a critical role in plaque development and may have the potential to track plaque progression. However, the diagnostic potential of these chemokine receptors has not been fully realized. On the basis of our previous work using a broad-spectrum peptide antagonist imaging 8 chemokine receptors together, the purpose of this study was to develop a targeted nanoparticle for sensitive and specific detection of these chemokine receptors in both a mouse vascular injury model and a spontaneously developed mouse atherosclerosis model.
  
  
  
  The viral macrophage inflammatory protein-II (vMIP-II) was conjugated to a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comblike nanoparticle through controlled conjugation and polymerization before radiolabeling with (64)Cu for PET imaging in an apolipoprotein E-deficient (ApoE(-/-)) mouse vascular injury model and a spontaneous ApoE(-/-) mouse atherosclerosis model. Histology, immunohistochemistry, and real-time reverse transcription polymerase chain reaction were performed to assess the plaque progression and upregulation of chemokine receptors.
  
  
  
  The chemokine receptor-targeted (64)Cu-vMIP-II-comb showed extended blood retention and improved biodistribution. PET imaging showed specific tracer accumulation at plaques in ApoE(-/-) mice, confirmed by competitive receptor blocking studies and assessment in wild-type mice. Histopathologic characterization showed the progression of plaque including size and macrophage population, corresponding to the elevated concentration of chemokine receptors and more importantly increased PET signals.
  
  
  
  This work provides a useful nanoplatform for sensitive and specific detection of chemokine receptors to assess plaque progression in mouse atherosclerosis models.
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri.
authors.forename: Hannah P
authors.initials: HP
authors.lastname: Luehmann
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri.
authors.forename: Lisa
authors.initials: L
authors.lastname: Detering
authors.affiliation: Department of Materials, Chemistry and Biochemistry, University of California, Santa Barbara, California; and.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Fors
authors.affiliation: Department of Materials, Chemistry and Biochemistry, University of California, Santa Barbara, California; and.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Pressly
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri.
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Woodard
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, Missouri.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gropler
authors.affiliation: Department of Materials, Chemistry and Biochemistry, University of California, Santa Barbara, California; and.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Hawker
authors.affiliation: Department of Radiology, Washington University, St. Louis, Missouri liuyo@mir.wustl.edu.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D018925:Chemokines / Q000737:chemistry / Q000493:pharmacokinetics; D003301:Copper Radioisotopes; D007249:Inflammation / Q000000981:diagnostic imaging*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053758:Nanoparticles; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000473:pathology; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
chemical_list: D001057:Apolipoproteins E; D018925:Chemokines; D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; D019707:Receptors, Chemokine; C108059:vMIP-II
keywords: PET/CT; atherosclerosis; chemokine receptor; nanoparticle; viral macrophage inflammatory protein-II