P1216Evaluation of alphavbeta3 integrin-targeted positron emission tomography and photoacoustic tracer for imaging of carotid plaque in apoE–/– mice

Abstract Background Cardiovascular disease is the leading cause of death in the world. The majority of cardiovascular events result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. The integrin αVβ3 is expressed by activated macrophages and endothelial cells in atherosclerotic lesions and thus is a marker of high-risk plaques. Therefore, 89Zr-RGD-melanin nanoparticle (MNP) positron emission tomography (PET)/photoacoustic imaging (PAI) imaging of αVβ3 expression in plaques might provide a novel noninvasive biomarker of plaque vulnerability. Purpose In this study, the intrinsic photoacoustic signals and the native strong chelating properties with metal ions of MNP, positron-emitting metal ions 89Zr and αVβ3 integrins targeting ability of cyclic c (RGDfC) peptide was employed to construct an efficient nanoplatform. And we evaluated the feasibility of 89Zr-RGD-MNP PET/PAI of αVβ3 expression in vivo and in vitro. Methods We conjugated αVβ3 integrins, cyclic c (RGDfC) peptide, to MNP and chelated the long-lived positron-emitting nuclide 89Zr. The bio-stability and targeting action was detected in macrophages. And the PET/PAI imaging was performed in apoE−/− mice with partial carotid ligation leading to atherosclerosis. In PET imaging, tracer uptake was measured in the stenotic areas of the carotid arteries, as well as on the contralateral side at different time points in vivo. In PAI, photoacoustic signal was measured in the atherosclerosis of the carotid arteries in vivo. Melanin staining and immunohistochemistry of αVβ3 expression were detected in atherosclerosis of the carotid arteries. Results 89Zr-RGD-MNP showed excellent bio-stability and targeting action. PET imaging showed specific tracer accumulation at plaques in the left carotid artery, confirmed by competitive receptor blocking studies and the contrast in the right carotid artery. In the biodistribution studies, the left carotid (5.29%±0.78%) showed higher uptake than the right carotid (2.11%±1.55%). PAI showed the PA signal in the surgery group (452±85 a.u.) were stronger than the control (156±45 a.u.) and blocking group (254±66 a.u). The result was consistent with PET imaging and the presence of nanoparticles, as indicated by pathological examinations. These results presented good in vivo multimodality imaging (PET/PAI) properties. Conclusions We have developed 89Zr-labeled atherosclerotic plaques imaging agents based on the natural melanin nanoparticle. 89Zr-RGD-MNP demonstrates specific tracer accumulation in mice atherosclerotic carotid plaques. In this model, its uptake was associated with αVβ3 expression. 89Zr-RGD-MNP is a potential tracer for noninvasive imaging in atherosclerosis. Acknowledgement/Funding National Natural Science Foundation of China 81770452, 81470401