Design and Modular Construction of a Polymeric Nanoparticle for Targeted Atherosclerosis Positron Emission Tomography Imaging: A Story of 25% 64Cu-CANF-Comb

Woodard, P. K., Liu, Y., Pressly, E. D., Luehmann, H. P., Detering, L., Sultan, D. E., Laforest, R., McGrath, A. J., Gropler, R. J., Hawker, C. J.
Pharm Res
33, 2400-2410

Purpose To assess the physicochemical properties, pharmacokinetic profiles, and in vivo positron emission tomography (PET) imaging of natriuretic peptide clearance receptors (NPRC) expressed on atherosclerotic plaque of a series of targeted, polymeric nanoparticles.

Methods To control their structure, non-targeted and targeted polymeric (comb) nanoparticles, conjugated with various amounts of c-atrial natriuretic peptide (CANF, 0, 5, 10 and 25%), were synthesized by controlled and modular chemistry. In vivo pharmacokinetic evaluation of these nanoparticles was performed in wildtype (WT) C57BL/6 mice after 64Cu radiolabeling. PET imaging was performed on an apolipoprotein E–deficient (ApoE−/− ) mouse atherosclerosis model to assess the NPRC targeting efficiency. For comparison, an in vivo blood metabolism study was carried out in WT mice.

Results All three 64Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted 64Cu-comb. Of the three nanoparticles, the 25% 64Cu-CANF-comb demonstrated the best NPRC targeting specificity and sensitivity in ApoE−/− mice. Metabolism studies showed that the radiolabeled CANFcomb was stable in blood up to 9 days. Histopathological analyses confirmed the up-regulation of NPRC along the progression of atherosclerosis.

Conclusion The 25% 64Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status