Matthias Nahrendorf1,2,3,4, Friedrich Felix Hoyer1,2, Anu E Meerwaldt5,6, Mandy M T van Leent5,7, Max L Senders5,7, Claudia Calcagno5, Philip M Robson5, George Soultanidis5, Carlos Pérez-Medina5,8, Abraham J P Teunissen5, Yohana C Toner5, Kiyotake Ishikawa9, Kenneth Fish9, Ken Sakurai5, Esther M van Leeuwen5,6, Emma D Klein5, Alexandros Marios Sofias5,10, Thomas Reiner11,12, David Rohde1,2, Aaron D Aguirre1,3,13, Gregory Wojtkiewicz1, Stephen Schmidt1, Yoshiko Iwamoto1, David Izquierdo-Garcia14, Peter Caravan14, Filip K Swirski1,2, Ralph Weissleder1,2,14,15, Willem J M Mulder5,16,7,17. 1. Center for Systems Biology (M.N., F.F.H., D.R., A.D.A., G.W., S.S., Y.I., F.K.S., R.W.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston. 2. Department of Radiology (M.N., F.F.H., D.R., F.K.S., R.W.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston. 3. Cardiovascular Research Center (M.N., A.D.A.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston. 4. Department of Internal Medicine I, University Hospital Wuerzburg, Germany (M.N.). 5. Biomedical Engineering and Imaging Institute (A.E.M., M.M.T.v.L., M.L.S., C.C., P.M.R., G.S., C.P.-M., A.J.P.T., Y.C.T., K.S., E.M.v.L., E.D.K., A.M.S., W.J.M.M.), Icahn School of Medicine at Mount Sinai, New York, NY. 6. Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, the Netherlands (A.E.M., E.M.v.L.). 7. Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands (M.M.T.v.L., M.L.S., W.J.M.M.). 8. Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (C.P.-M.). 9. Department of Cardiology, Cardiovascular Research Center (K.I., K.F.), Icahn School of Medicine at Mount Sinai, New York, NY. 10. Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway (A.M.S.). 11. Department of Radiology and Chemical Biology Program, Memorial Sloan- Kettering Cancer Center, New York, NY (T.R.). 12. Department of Radiology, Weill Cornell Medical College, New York, NY (T.R.). 13. Wellman Center for Photomedicine (A.D.A.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston. 14. Institute for Innovation in Imaging, A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown (D.I.-G., P.C., R.W.). 15. Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.). 16. Department of Oncological Sciences (W.J.M.M.), Icahn School of Medicine at Mount Sinai, New York, NY. 17. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, the Netherlands (W.J.M.M.).
Abstract
BACKGROUND: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases. METHODS: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer 64Cu-Macrin-a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose. RESULTS: PET imaging using 64Cu-Macrin faithfully reported accumulation of macrophages in the heart and lung of mice with myocardial infarction, sepsis, or pneumonia. Flow cytometry and confocal microscopy detected the near-infrared fluorescent version of the nanoparticle (VT680Macrin) primarily in tissue macrophages. In 5-day-old mice, 64Cu-Macrin PET imaging quantified physiologically more numerous cardiac macrophages. Upon intravenous administration of 64Cu-Macrin in rabbits and pigs, we detected heightened macrophage numbers in the infarcted myocardium, inflamed lung regions, and atherosclerotic plaques using a clinical PET/magnetic resonance imaging scanner. Toxicity studies in rats and human dosimetry estimates suggest that 64Cu-Macrin is safe for use in humans. CONCLUSIONS: Taken together, these results indicate 64Cu-Macrin could serve as a facile PET nanotracer to survey spatiotemporal macrophage dynamics during various physiological and pathological conditions. 64Cu-Macrin PET imaging could stage inflammatory cardiovascular disease activity, assist disease management, and serve as an imaging biomarker for emerging macrophage-targeted therapeutics.
BACKGROUND: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases. METHODS: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer 64Cu-Macrin-a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose. RESULTS: PET imaging using 64Cu-Macrin faithfully reported accumulation of macrophages in the heart and lung of mice with myocardial infarction, sepsis, or pneumonia. Flow cytometry and confocal microscopy detected the near-infrared fluorescent version of the nanoparticle (VT680Macrin) primarily in tissue macrophages. In 5-day-old mice, 64Cu-Macrin PET imaging quantified physiologically more numerous cardiac macrophages. Upon intravenous administration of 64Cu-Macrin in rabbits and pigs, we detected heightened macrophage numbers in the infarcted myocardium, inflamed lung regions, and atherosclerotic plaques using a clinical PET/magnetic resonance imaging scanner. Toxicity studies in rats and human dosimetry estimates suggest that 64Cu-Macrin is safe for use in humans. CONCLUSIONS: Taken together, these results indicate 64Cu-Macrin could serve as a facile PET nanotracer to survey spatiotemporal macrophage dynamics during various physiological and pathological conditions. 64Cu-Macrin PET imaging could stage inflammatory cardiovascular disease activity, assist disease management, and serve as an imaging biomarker for emerging macrophage-targeted therapeutics.
Authors: Friedrich Felix Hoyer; Kamila Naxerova; Maximilian J Schloss; Maarten Hulsmans; Anil V Nair; Partha Dutta; David M Calcagno; Fanny Herisson; Atsushi Anzai; Yuan Sun; Gregory Wojtkiewicz; David Rohde; Vanessa Frodermann; Katrien Vandoorne; Gabriel Courties; Yoshiko Iwamoto; Christopher S Garris; David L Williams; Sylvie Breton; Dennis Brown; Michael Whalen; Peter Libby; Mikael J Pittet; Kevin R King; Ralph Weissleder; Filip K Swirski; Matthias Nahrendorf Journal: Immunity Date: 2019-11-12 Impact factor: 31.745
Authors: Won Woo Lee; Brett Marinelli; Anja M van der Laan; Brena F Sena; Rostic Gorbatov; Florian Leuschner; Partha Dutta; Yoshiko Iwamoto; Takuya Ueno; Mark P V Begieneman; Hans W M Niessen; Jan J Piek; Claudio Vinegoni; Mikael J Pittet; Filip K Swirski; Ahmed Tawakol; Marcelo Di Carli; Ralph Weissleder; Matthias Nahrendorf Journal: J Am Coll Cardiol Date: 2012-01-10 Impact factor: 24.094
Authors: M E Kooi; V C Cappendijk; K B J M Cleutjens; A G H Kessels; P J E H M Kitslaar; M Borgers; P M Frederik; M J A P Daemen; J M A van Engelshoven Journal: Circulation Date: 2003-04-28 Impact factor: 29.690
Authors: Arin B Aurora; Enzo R Porrello; Wei Tan; Ahmed I Mahmoud; Joseph A Hill; Rhonda Bassel-Duby; Hesham A Sadek; Eric N Olson Journal: J Clin Invest Date: 2014-02-24 Impact factor: 14.808
Authors: James T Thackeray; Thorsten Derlin; Arash Haghikia; L Christian Napp; Yong Wang; Tobias L Ross; Andreas Schäfer; Jochen Tillmanns; Hans J Wester; Kai C Wollert; Johann Bauersachs; Frank M Bengel Journal: JACC Cardiovasc Imaging Date: 2015-11-11