| Title | Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis. |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | Senders ML, Hernot S, Carlucci G, van de Voort JC, Fay F, Calcagno C, Tang J, Alaarg A, Zhao Y, Ishino S, Palmisano A, Boeykens G, Meerwaldt AE, Sanchez-Gaytan BL, Baxter S, Zendman L, Lobatto ME, Karakatsanis NA, Robson PM, Broisat A, Raes G, Lewis JS, Tsimikas S, Reiner T, Fayad ZA, Devoogdt N, Mulder WJM, Pérez-Medina C |
| Journal | JACC Cardiovasc Imaging |
| Volume | 12 |
| Issue | 10 |
| Pagination | 2015-2026 |
| Date Published | 2019 10 |
| ISSN | 1876-7591 |
| Keywords | Animals, Atherosclerosis, Disease Models, Animal, Disease Progression, Early Diagnosis, Genetic Predisposition to Disease, Lectins, C-Type, Mannose Receptor, Mannose-Binding Lectins, Mice, Knockout, ApoE, Multimodal Imaging, Multiparametric Magnetic Resonance Imaging, Phenotype, Plaque, Atherosclerotic, Positron-Emission Tomography, Rabbits, Radiopharmaceuticals, Receptors, Cell Surface, Scavenger Receptors, Class E, Single-Domain Antibodies, Vascular Cell Adhesion Molecule-1 |
| Abstract | 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 (Cu), 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 (Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by Ga-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 (F)-labeled fluorodeoxyglucose (F-FDG) and F-sodium fluoride (F-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. |
| DOI | 10.1016/j.jcmg.2018.07.027 |
| Alternate Journal | JACC Cardiovasc Imaging |
| PubMed ID | 30343086 |
| PubMed Central ID | PMC6461528 |
| Grant List | R01 HL125703 / HL / NHLBI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R01 EB009638 / EB / NIBIB NIH HHS / United States R01 HL118440 / HL / NHLBI NIH HHS / United States P41 EB017183 / EB / NIBIB NIH HHS / United States R01 HL071021 / HL / NHLBI NIH HHS / United States P01 HL131478 / HL / NHLBI NIH HHS / United States |