Assessment of natriuretic peptide clearance receptor (NPR-C) targeted nanoparticles for atherosclerosis PET imaging

Objectives The goal of this study was to assess the imaging capability of C-type atrial natriuretic factor (CANF) conjugated nanoparticles to target the natriuretic peptide clearance receptor (NPR-C) up-regulated in a clinically relevant model of atherosclerosis.

Methods CANF-Comb nanoparticles were prepared through modular construction with controlled functionalities for PET imaging of NPR-C receptor via radiolabeling with 64Cu. The efficiency of the construct was demonstrated in ApoE-/- mice fed a high cholesterol diet to form spontaneous atherosclerotic lesions in the aorta. Age-matched C57BL6 mice fed a normal diet were the control animals. PET/CT imaging was performed at multiple time points to follow the progression of disease. The aortic arteries were collected post scan for histopathological examination and RT-PCR analysis. Blocking studies were also performed to confirm targeting specificity.

Results PET studies show greater uptake of 64Cu-CANF-Comb in the ApoE-/- mice compared to the C57BL6 mice on 18 weeks of diet with standard uptake values (SUV) of 5.35 (SD = 1.01) and 3.30 (SD = 1.13), respectively (P < 0.03, n = 6). PET competitive blocking studies significantly reduced the tracer uptake (SUV = 3.94, SD = 0.25, P < 0.02, n = 6) and confirmed receptor-mediated tracer uptake in the plaque. Longitudinal imaging studies showed that NPR-C was up-regulated at an early stage of plaque development, which was also confirmed by quantitative RT-PCR analysis.

Conclusions PET/CT imaging showed the capability of the 64Cu-CANF-Comb to image plaque in a pre-clinical model of spontaneous atherosclerosis development. Its in vivo pharmacokinetics and plaque uptake indicate translational potential as a PET imaging agent for early-stage atherosclerosis in humans.

Research Support This work is supported by the National Institutes of Health as a Program of Excellence in Nanotechnology (HHSN268201000046C).