Author + information
- Received December 6, 2017
- Revision received June 11, 2018
- Accepted July 12, 2018
- Published online October 7, 2019.
- Max L. Senders, MDa,b,
- Sophie Hernot, PhDc,
- Giuseppe Carlucci, PhDd,e,
- Jan C. van de Voort, BSa,
- Francois Fay, PhDa,f,
- Claudia Calcagno, MD, PhDa,
- Jun Tang, PhDe,
- Amr Alaarg, PhDa,g,
- Yiming Zhao, PhDa,
- Seigo Ishino, PhDa,
- Anna Palmisano, MDa,h,
- Gilles Boeykens, BSa,
- Anu E. Meerwaldt, MSa,
- Brenda L. Sanchez-Gaytan, PhDa,
- Samantha Baxter, MHSa,
- Laura Zendman, MSa,
- Mark E. Lobatto, MD, PhDi,
- Nicolas A. Karakatsanis, PhDa,
- Philip M. Robson, PhDa,
- Alexis Broisat, PhDj,
- Geert Raes, PhDk,l,
- Jason S. Lewis, PhDe,m,n,
- Sotirios Tsimikas, MDo,
- Thomas Reiner, PhDe,m,
- Zahi A. Fayad, PhDa,
- Nick Devoogdt, PhDc,
- Willem J.M. Mulder, PhDa,b,∗∗∗ ( and )
- Carlos Pérez-Medina, PhDa,∗∗ ()
- aTranslational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- bDepartment of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands
- cIn Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium
- dBernard and Irene Schwarz Center for Biomedical Imaging, New York University, New York, New York
- eDepartment of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
- fDepartment of Chemistry, York College of The City University of New York, New York, New York
- gDepartment of Biomaterials Science and Technology, Technical Medical Centre. University of Twente, Enschede, the Netherlands
- hUnit of Clinical Research in Radiology, Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy
- iDepartment of Radiology, Academic Medical Center, Amsterdam, the Netherlands
- jBioclinic Radiopharmaceutics Laboratory, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S 1039, Grenoble, France
- kResearch Group of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- lLaboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Inflammation Research Center, Ghent, Belgium
- mDepartment of Radiology, Weill Cornell Medical College, New York, New York
- nMolecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
- oDivision of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California-La Jolla, San Diego, California
- ↵∗Address for correspondence:
Dr. Carlos Pérez-Medina, Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029.
- ↵∗∗Dr. Willem J.M. Mulder, Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, New York 10029.
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.
↵∗ Drs. Mulder and Pérez-Medina contributed equally to this work and are joint senior authors.
This work was supported by the National Institutes of Health grants R01 EB009638, P01 HL131478 (to Dr. Fayad), R01 HL125703, R01 HL118440 (to Dr. Mulder), P30 CA008748, the American Heart Association 16SDG31390007 (to Dr. Pérez-Medina), 17PRE33660729 (to Dr. Senders), the Netherlands Organization for Scientific Research Nederlandse Organisatie voor Wetenschappelijk Onderzoek Vidi (to Dr. Mulder), and the “De Drie Lichten” Foundation in the Netherlands (to Dr. Senders). The authors also thank the Center for Molecular Imaging and Nanotechnology for financial support (to Dr. Reiner). Drs. Hernot, Raes and Devoogdt are coinventors on patent US961733B2, and Drs. Broisat and Devoogdt on patent WO2013026878A1 related to the use of anti-MMR and anti-VCAM1 nanobodies, respectively, in cardiovascular diseases. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received December 6, 2017.
- Revision received June 11, 2018.
- Accepted July 12, 2018.
- 2019 The Authors