Macrophage PET imaging in mouse models of cardiovascular disease and cancer with an apolipoprotein-inspired radiotracer

Yohana C Toner; Geoffrey Prévot; Mandy M T van Leent; Jazz Munitz; Roderick Oosterwijk; Anna Vera D Verschuur; Yuri van Elsas; Vedran Peric; Rianne J F Maas; Anna Ranzenigo; Judit Morla-Folch; William Wang; Martin Umali; Anne de Dreu; Jessica Chimene Fernandes; Nathaniel A T Sullivan; Alexander Maier; Christian Mason; Thomas Reiner; Zahi A Fayad; Willem J M Mulder; Abraham J P Teunissen; Carlos Pérez-Medina

doi:10.1038/s44303-024-00009-3

Macrophage PET imaging in mouse models of cardiovascular disease and cancer with an apolipoprotein-inspired radiotracer

Npj Imaging. 2024;2(1):12. doi: 10.1038/s44303-024-00009-3. Epub 2024 May 15.

Authors

Yohana C Toner^#^{1

2

3}, Geoffrey Prévot^#^{1

2}, Mandy M T van Leent^{1

2

4}, Jazz Munitz^{1

2}, Roderick Oosterwijk^{1

2

5}, Anna Vera D Verschuur^{1

2}, Yuri van Elsas^{1

2

3}, Vedran Peric^{1

2

5}, Rianne J F Maas^{1

2

3}, Anna Ranzenigo^{1

2}, Judit Morla-Folch^{1

2}, William Wang^{1

2}, Martin Umali^{1

2}, Anne de Dreu⁵, Jessica Chimene Fernandes^{1

2}, Nathaniel A T Sullivan^{1

2}, Alexander Maier^{1

2

6}, Christian Mason⁷, Thomas Reiner^{7

8

9}, Zahi A Fayad^{1

2

4}, Willem J M Mulder^{1

2

3

5}, Abraham J P Teunissen^{1

2

4

10}, Carlos Pérez-Medina^{1

2

11}

Affiliations

¹ BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA.
² Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY USA.
³ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
⁴ Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA.
⁵ Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
⁶ Department of Cardiology and Angiology, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁷ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
⁸ Department of Radiology, Weill Cornell Medical College, New York, NY USA.
⁹ Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY USA.
¹⁰ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA.
¹¹ Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

^# Contributed equally.

Abstract

Macrophages are key inflammatory mediators in many pathological conditions, including cardiovascular disease (CVD) and cancer, the leading causes of morbidity and mortality worldwide. This makes macrophage burden a valuable diagnostic marker and several strategies to monitor these cells have been reported. However, such strategies are often high-priced, non-specific, invasive, and/or not quantitative. Here, we developed a positron emission tomography (PET) radiotracer based on apolipoprotein A1 (ApoA1), the main protein component of high-density lipoprotein (HDL), which has an inherent affinity for macrophages. We radiolabeled an ApoA1-mimetic peptide (mA1) with zirconium-89 (⁸⁹Zr) to generate a lipoprotein-avid PET probe (⁸⁹Zr-mA1). We first characterized ⁸⁹Zr-mA1's affinity for lipoproteins in vitro by size exclusion chromatography. To study ⁸⁹Zr-mA1's in vivo behavior and interaction with endogenous lipoproteins, we performed extensive studies in wildtype C57BL/6 and Apoe^-/- hypercholesterolemic mice. Subsequently, we used in vivo PET imaging to study macrophages in melanoma and myocardial infarction using mouse models. The tracer's cell specificity was assessed by histology and mass cytometry (CyTOF). Our data show that ⁸⁹Zr-mA1 associates with lipoproteins in vitro. This is in line with our in vivo experiments, in which we observed longer ⁸⁹Zr-mA1 circulation times in hypercholesterolemic mice compared to C57BL/6 controls. ⁸⁹Zr-mA1 displayed a tissue distribution profile similar to ApoA1 and HDL, with high kidney and liver uptake as well as substantial signal in the bone marrow and spleen. The tracer also accumulated in tumors of melanoma-bearing mice and in the ischemic myocardium of infarcted animals. In these sites, CyTOF analyses revealed that ^natZr-mA1 was predominantly taken up by macrophages. Our results demonstrate that ⁸⁹Zr-mA1 associates with lipoproteins and hence accumulates in macrophages in vivo. ⁸⁹Zr-mA1's high uptake in these cells makes it a promising radiotracer for non-invasively and quantitatively studying conditions characterized by marked changes in macrophage burden.

Keywords: Biomedical engineering; Imaging techniques and agents; Positron-emission tomography.

Grants and funding

R01 CA220234/CA/NCI NIH HHS/United States