TY - JOUR
T1 - Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis
AU - Senders, Max L.
AU - Hernot, Sophie
AU - Carlucci, Giuseppe
AU - van de Voort, Jan C.
AU - Fay, Francois
AU - Calcagno, Claudia
AU - Tang, Jun
AU - Alaarg, Amr
AU - Zhao, Yiming
AU - Ishino, Seigo
AU - Palmisano, Anna
AU - Boeykens, Gilles
AU - Meerwaldt, Anu E.
AU - Sanchez-Gaytan, Brenda L.
AU - Baxter, Samantha
AU - Zendman, Laura
AU - Lobatto, Mark E.
AU - Karakatsanis, Nicolas A.
AU - Robson, Philip M.
AU - Broisat, Alexis
AU - Raes, Geert
AU - Lewis, Jason S.
AU - Tsimikas, Sotirios
AU - Reiner, Thomas
AU - Fayad, Zahi A.
AU - Devoogdt, Nick
AU - Mulder, Willem J. M.
AU - Pérez-Medina, Carlos
PY - 2019/10
Y1 - 2019/10
N2 - Objectives: This study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers. Background: Noninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated. Methods: We screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 (64Cu), were extensively evaluated in Apoe–/– mice and atherosclerotic rabbits using a combination of in vivo PET/MRI readouts and ex vivo radioactivity counting, autoradiography, and histological analyses. Results: The 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 (68Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by 68Ga-MMR–PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 (18F)-labeled fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features. Conclusions: We have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocol that allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approach allows the multiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials.
AB - Objectives: This study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers. Background: Noninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated. Methods: We screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 (64Cu), were extensively evaluated in Apoe–/– mice and atherosclerotic rabbits using a combination of in vivo PET/MRI readouts and ex vivo radioactivity counting, autoradiography, and histological analyses. Results: The 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 (68Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by 68Ga-MMR–PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 (18F)-labeled fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features. Conclusions: We have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocol that allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approach allows the multiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85055121077&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30343086
U2 - https://doi.org/10.1016/j.jcmg.2018.07.027
DO - https://doi.org/10.1016/j.jcmg.2018.07.027
M3 - Article
C2 - 30343086
SN - 1936-878X
VL - 12
SP - 2015
EP - 2026
JO - JACC. Cardiovascular imaging
JF - JACC. Cardiovascular imaging
IS - 10
ER -