Assessment of Targeted Nanoparticle Assemblies for Atherosclerosis Imaging with Positron Emission Tomography and Potential for Clinical Translation

Nanoparticles have been assessed in preclinical models of atherosclerosis for detection of plaque complexity and treatment. However, their successful clinical translation has been hampered by less than satisfactory plaque detection, and lack of a general strategy for assessing the translational potential of nanoparticles. Herein, nanoparticles based on comb-copolymer assemblies were synthesized through a modular construction approach with precise control over the conjugation of multiple functional building blocks for in vivo evaluation. This high level of design control also allows physicochemical properties to be varied in a controllable fashion. Through conjugation of c-atrial natriuretic factor (CANF) peptide and radiolabeling with (64)Cu, the (64)Cu-CANF-Comb nanoparticle was assessed for plaque imaging by targeting natriuretic peptide clearance receptor (NPRC) in a double-injury atherosclerosis model in rabbits. The extended blood circulation and improved binding capacity of (64)Cu-CANF-Comb nanoparticles afforded sensitive and specific detection of NPRC upregulated in atherosclerotic lesions by positron emission tomography (PET) at intervals during the progression of disease. Ex vivo tissue validation using autoradiography and immunostaining on human carotid endarterectomy specimens demonstrated specific binding of (64)Cu-CANF-Comb to human NPRC receptors. Taken together, this study not only shows the potential of NPRC-targeted (64)Cu-CANF-Comb nanoparticles for increased sensitivity to an epitope that increases during atherosclerosis plaque development, but also provides a useful strategy for the general design and assessment of translational potential of nanoparticles in cardiovascular imaging.