HAP-Multitag, a PET and Positive MRI Contrast Nanotracer for the Longitudinal Characterization of Vascular Calcifications in Atherosclerosis

Vascular microcalcifications are associated with atherosclerosis plaque instability and, therefore, to increased mortality. Because of this key role, several imaging probes have been developed for their in vivo identification. Among them, [18F]FNa is the gold standard, showing a large uptake in the whole skeleton by positron emission tomography. Here, we push the field toward the combined anatomical and functional early characterization of atherosclerosis. For this, we have developed hydroxyapatite (HAP)-multitag, a bisphosphonate- functionalized 68Ga core-doped magnetic nanoparticle showing high affinity toward most common calcium salts present in microcalcifications, particularly HAP. We characterized this interaction in vitro and in vivo, showing a massive uptake in the atherosclerotic lesion identified by positron emission tomography (PET) and positive contrast magnetic resonance imaging (MRI). In addition, this accumulation was found to be dependent on the calcification progression, with a maximum uptake in the microcalcification stage. These results confirmed the ability of HAP-multitag to identify vascular calcifications by PET/(T1)MRI during the vulnerable stages of the plaque progression.This work was supported by the Spanish Ministry of Science (grant nos. SAF2016-79593-P, RED2018-102469-T, and PID2019-104059RB-I00) and from the Gobierno Vasco, Dpto. Industria, Innovación, Comercio y Turismo under the ELKARTEK Program (grant no. KK-2019/bmG19). JR-C received funding from the BBVA Foundation (Ayudas a Equipos de investigación científica Biomedicina 2018). The CNIC is supported by the MICINN and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MICINN award SEV-2015-0505). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agencygrant no. MDM-2017-0720. L.G. acknowledges financial support from the Ramón y Cajal program (RYC-2014-15512 0)Peer reviewe