Nanoparticle positron emission tomography/computed tomography imaging of chemokine receptor CCR5 in atherosclerosis

Objectives We have demonstrated the specific PET imaging of CCR5 important to atherosclerosis with 64Cu-DAPTA peptide tracer in a vascular injury model. Herein, we aim to demonstrate improved CCR5 detection specificity and sensitivity with DAPTA peptides conjugated nanoparticles in a clinically relevant model of atherosclerosis.

Methods The DAPTA-Comb nanoparticles were prepared with controlled conjugation of DAPTA peptides and DOTA. Biodistribution of 64Cu-DAPTA-Comb was performed in C57 mice. Aortic artery (AA) CCR5 detection efficiency and specificity was assessed in ApoE-/- mice on western diet and age-matched C57 mice on normal chow with PET/CT, respectively. Histopathological characterization of CCR5 was performed on the AA after scan. PET blocking studies were performed to evaluate CCR5 targeting specificity.

Results Biodistribution showed extended blood circulation and reduced hepatic and splenic accumulation of 64Cu-DAPTA-Comb relative to 64Cu-Comb and 64Cu-DAPTA peptide. 64Cu-DAPTA-Comb showed significantly higher AA uptake (7.5 ± 1.0 %ID/g, p<0.001, n=6) than either 64Cu-DAPTA peptide (0.8 ± 0.1 %ID/g) or 64Cu-Comb (3.5 ± 0.7 %ID/g, p<0.005, n=6) in the ApoE-/- mice. PET blocking studies demonstrated significantly (3.7 ± 0.5 %ID/g, p<0.005, n=6) decreased 64Cu-DAPTA-Comb AA uptake. Longitudinal imaging studies demonstrated CCR5 detection efficiency and specificity of 64Cu-DAPTA-Comb during the progression of disease, which was confirmed by both RT-PCR and immunohistochemistry.

Conclusions The 64Cu-DAPTA-Comb affords sensitive and specific imaging of CCR5 that is superior to 64Cu-DAPTA peptide in atherosclerotic lesion. Its superior pharmacokinetics and targeting efficiency make it a promising candidate tracer for further evaluation.

Research Support This work is supported by the NHLBI Program of Excellence in Nanotechnology (HHSN268201000046C).