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

Abstract

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, [ 18 F]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 bisphosphonatefunctionalized 68 Ga 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/(T 1 )MRI during the vulnerable stages of the plaque progression.

A Comparative Study of Ultrasmall Calcium Carbonate Nanoparticles for Targeting and Imaging Atherosclerotic Plaque

“…We chose alendronate for CC functionalization because it is a bisphosphonate ligand that has recently been applied in imaging microcalcifications. 16 Monocyte-derived macrophages play a critical role in the pathogenesis and progression of atherosclerosis. 46 However, as macrophages are a heterogeneous population of cells, different subtypes could exhibit either pro-or antiatherosclerotic properties.…”

“…Bisphosphonates’ affinity for HAP stems from their chemical resemblance to pyrophosphates, which regulate HAP formation in the body. We chose alendronate for CC functionalization because it is a bisphosphonate ligand that has recently been applied in imaging microcalcifications …”

“…While there is consensus that MRI and PET are the most practical and comprehensive methods for imaging the plaque in vivo , , the lack of specificity of NP accumulation in most proposed contrast agents remains a challenge for early and plaque vulnerability diagnosis. − Different preclinical models of atherosclerosis have confirmed the unspecific accumulation of liposomes and poly­(lactic- co -glycolic acid) (PLGA) NPs in the plaque. , To develop advanced clinical diagnostic tools, specific accumulation of nanoparticles only in the presence of disease-specific hallmarks indicating the type of atherosclerotic lesion (e.g., intimal thickening, fibroatheroma, plaque erosion) is required . Targeted imaging with NPs offers a promising approach to reveal processes such as the enlargement of the necrotic core, the presence of microcalcifications, or the reduction of the fibrotic cap. ,, As a result, much scientific effort is focused on the development of targeted NP imaging for atherosclerosis.…”

Engineering molecular nanoprobes to target early atherosclerosis: Precise diagnostic tools and promising therapeutic carriers

“…Importantly, these imaging probes are capable of providing simultaneous signals in both modalities, i.e. PET/MRI 97 . In summary, PET/MR dual-modality imaging allows for non-invasive studies of atherosclerotic progression, and relevant molecular mechanisms as well.…”

“…Positron emission tomography (PET) is particularly suitable for the non-invasive and quantitative characterization of macrophage-mediated inflammation, vascular calcifications as well as angiogenesis in atherosclerosis owing to the high tissue penetration and superior sensitivity [96][97][98]. However, current PET imaging agents are not targeted.…”