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 BroisatGeert Raes, Jason S. Lewis, Sotirios Tsimikas, Thomas Reiner, Zahi A. Fayad, Nick Devoogdt, Willem J.M. Mulder, Carlos Pérez-Medina*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)
4 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)2015-2026
Number of pages12
JournalJACC: Cardiovascular Imaging
Volume12
Issue number10
DOIs
Publication statusPublished - Oct 2019

Keywords

  • atherosclerosis
  • molecular imaging
  • nanobody
  • PET/MRI

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