CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography

Mol Pharm. 2021 Mar 1;18(3):1386-1396. doi: 10.1021/acs.molpharmaceut.0c01183. Epub 2021 Feb 16.

Abstract

Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64Cu radiolabeling showed extended blood circulation of 64Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE-/-) showed that the three 64Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE-/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

Keywords: CCR5; atherosclerosis; macrophage; nanoparticle; positron emission tomography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alanine / metabolism
  • Animals
  • Apolipoproteins E / metabolism
  • Atherosclerosis / diagnostic imaging*
  • Atherosclerosis / metabolism*
  • Chemokines / metabolism
  • Copper Radioisotopes / metabolism
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nanoparticles / administration & dosage*
  • Plaque, Atherosclerotic / diagnostic imaging
  • Plaque, Atherosclerotic / metabolism
  • Positron Emission Tomography Computed Tomography / methods
  • Radiopharmaceuticals / metabolism
  • Receptors, CCR5 / metabolism*

Substances

  • Apolipoproteins E
  • CCR5 protein, mouse
  • Chemokines
  • Copper Radioisotopes
  • D-Ala-peptide T-amide
  • Radiopharmaceuticals
  • Receptors, CCR5
  • Alanine