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

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Juan Pellico , Irene Fernández-barahona, Jesús Ruiz-Cabello, Lucía Gutiérrez, María Muñoz-Hernando, María J. Sánchez-Guisado, Irati Aiestaran-Zelaia, Lydia Martínez-Parra, Ignacio Rodríguez, Jacob Fog Bentzon, Fernando Herranz

Original languageEnglish
Pages (from-to)45279-45290
Number of pages12
JournalACS Applied Materials and Interfaces
Issue number38
Early online date16 Sep 2021
Accepted/In press9 Sep 2021
E-pub ahead of print16 Sep 2021
Published29 Sep 2021

Bibliographical note

Funding Information: 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 Agency—grant no. MDM-2017-0720. L.G. acknowledges financial support from the Ramón y Cajal program (RYC-2014-15512 0). Publisher Copyright: © 2021 The Authors. Published by American Chemical Society


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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.

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