Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis

Max L Senders; Sophie Hernot; Giuseppe Carlucci; Jan C van de Voort; Francois Fay; Claudia Calcagno; Jun Tang; Amr Alaarg; Yiming Zhao; Seigo Ishino; Anna Palmisano; Gilles Boeykens; Anu E Meerwaldt; Brenda L Sanchez-Gaytan; Samantha Baxter; Laura Zendman; Mark E Lobatto; Nicolas A Karakatsanis; Philip M Robson; Alexis Broisat; Geert Raes; Jason S Lewis; Sotirios Tsimikas; Thomas Reiner; Zahi A Fayad; Nick Devoogdt; Willem J M Mulder; Carlos Pérez-Medina

doi:10.1016/j.jcmg.2018.07.027

Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis

JACC Cardiovasc Imaging. 2019 Oct;12(10):2015-2026. doi: 10.1016/j.jcmg.2018.07.027. Epub 2018 Oct 17.

Authors

Max L Senders¹, Sophie Hernot², Giuseppe Carlucci³, Jan C van de Voort⁴, Francois Fay⁵, Claudia Calcagno⁴, Jun Tang⁶, Amr Alaarg⁷, Yiming Zhao⁴, Seigo Ishino⁴, Anna Palmisano⁸, Gilles Boeykens⁴, Anu E Meerwaldt⁴, Brenda L Sanchez-Gaytan⁴, Samantha Baxter⁴, Laura Zendman⁴, Mark E Lobatto⁹, Nicolas A Karakatsanis⁴, Philip M Robson⁴, Alexis Broisat¹⁰, Geert Raes¹¹, Jason S Lewis¹², Sotirios Tsimikas¹³, Thomas Reiner¹⁴, Zahi A Fayad⁴, Nick Devoogdt², Willem J M Mulder¹⁵, Carlos Pérez-Medina¹⁶

Affiliations

¹ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands.
² In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
³ Bernard and Irene Schwarz Center for Biomedical Imaging, New York University, New York, New York; Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
⁴ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
⁵ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Chemistry, York College of The City University of New York, New York, New York.
⁶ Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
⁷ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Biomaterials Science and Technology, Technical Medical Centre. University of Twente, Enschede, the Netherlands.
⁸ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Unit of Clinical Research in Radiology, Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy.
⁹ Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
¹⁰ Bioclinic Radiopharmaceutics Laboratory, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S 1039, Grenoble, France.
¹¹ Research Group of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Inflammation Research Center, Ghent, Belgium.
¹² Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Radiology, Weill Cornell Medical College, New York, New York; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
¹³ Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California-La Jolla, San Diego, California.
¹⁴ Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Radiology, Weill Cornell Medical College, New York, New York.
¹⁵ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: [email protected].
¹⁶ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: [email protected].

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 (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.

Keywords: PET/MRI; atherosclerosis; molecular imaging; nanobody.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis / diagnostic imaging*
Atherosclerosis / genetics
Atherosclerosis / immunology
Atherosclerosis / pathology
Disease Models, Animal
Disease Progression
Early Diagnosis
Genetic Predisposition to Disease
Lectins, C-Type / immunology
Mannose Receptor
Mannose-Binding Lectins / immunology
Mice, Knockout, ApoE
Multimodal Imaging
Multiparametric Magnetic Resonance Imaging*
Phenotype
Plaque, Atherosclerotic*
Positron-Emission Tomography*
Rabbits
Radiopharmaceuticals / administration & dosage*
Radiopharmaceuticals / pharmacokinetics
Receptors, Cell Surface / immunology
Scavenger Receptors, Class E / immunology
Single-Domain Antibodies / administration & dosage*
Single-Domain Antibodies / metabolism
Vascular Cell Adhesion Molecule-1 / immunology

Substances

Lectins, C-Type
Mannose Receptor
Mannose-Binding Lectins
Olr1 protein, mouse
Radiopharmaceuticals
Receptors, Cell Surface
Scavenger Receptors, Class E
Single-Domain Antibodies
Vascular Cell Adhesion Molecule-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding