Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease

Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with 18F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology.

[1]  Ralph Weissleder,et al.  Activatable magnetic resonance imaging agents for myeloperoxidase sensing: mechanism of activation, stability, and toxicity. , 2010, Journal of the American Chemical Society.

[2]  Mark D. Huffman,et al.  Executive Summary: Heart Disease and Stroke Statistics—2015 Update A Report From the American Heart Association , 2011, Circulation.

[3]  J. Mařı́k,et al.  Preparation of 18F-labeled peptides using the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition , 2011, Nature Protocols.

[4]  Ahmed Tawakol,et al.  In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. , 2006, Journal of the American College of Cardiology.

[5]  M. Wintermark,et al.  Validation of FDG Uptake in the Arterial Wall as an Imaging Biomarker of Atherosclerotic Plaques with 18F‐Fluorodeoxyglucose Positron Emission Tomography‐Computed Tomography (FDG‐PET/CT) , 2014, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[6]  I. Ial,et al.  Nature Communications , 2010, Nature Cell Biology.

[7]  J. Knuuti,et al.  Effects of age, diet, and type 2 diabetes on the development and FDG uptake of atherosclerotic plaques. , 2011, JACC. Cardiovascular imaging.

[8]  M. Nahrendorf,et al.  Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure , 2013, Science.

[9]  R. Weissleder,et al.  Advancing biomedical imaging , 2015, Proceedings of the National Academy of Sciences.

[10]  R. Weissleder,et al.  Imaging macrophages with nanoparticles. , 2014, Nature materials.

[11]  T. Xia,et al.  Understanding biophysicochemical interactions at the nano-bio interface. , 2009, Nature materials.

[12]  V. Dilsizian,et al.  18F-Fluorodeoxyglucose PET Imaging of Coronary Atherosclerosis and Plaque Inflammation , 2010, Current cardiology reports.

[13]  J. Min,et al.  Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. , 2015, JACC. Cardiovascular imaging.

[14]  P. Libby,et al.  Chigh Monocytes Depend on Nr 4 a 1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium , 2014 .

[15]  Greg M Thurber,et al.  18F labeled nanoparticles for in vivo PET-CT imaging. , 2009, Bioconjugate chemistry.

[16]  D. Mozaffarian,et al.  Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. , 2010, Circulation.

[17]  P. Libby,et al.  Activatable Magnetic Resonance Imaging Agent Reports Myeloperoxidase Activity in Healing Infarcts and Noninvasively Detects the Antiinflammatory Effects of Atorvastatin on Ischemia-Reperfusion Injury , 2008, Circulation.

[18]  F. Smith,et al.  COLORIMETRIC METHOD FOR DETER-MINATION OF SUGAR AND RELATED SUBSTANCE , 1956 .

[19]  S. Nekolla,et al.  PET/MRI early after myocardial infarction: evaluation of viability with late gadolinium enhancement transmurality vs. 18F-FDG uptake. , 2015, European heart journal cardiovascular Imaging.

[20]  R. Weissleder,et al.  Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice. , 2010, The Journal of clinical investigation.

[21]  Ralph Weissleder,et al.  Intravital imaging of cardiac function at the single-cell level , 2014, Proceedings of the National Academy of Sciences.

[22]  P. Libby,et al.  The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions , 2007, The Journal of experimental medicine.

[23]  Masatoshi Ishibashi,et al.  Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. , 2006, Journal of the American College of Cardiology.

[24]  C. Bremer,et al.  Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity , 2014, Nature Communications.

[25]  Charles P. Lin,et al.  Myocardial infarction accelerates atherosclerosis , 2012, Nature.

[26]  Ahmed Tawakol,et al.  PET/MRI of inflammation in myocardial infarction. , 2012, Journal of the American College of Cardiology.

[27]  Mark D. Huffman,et al.  Heart Disease and Stroke Statistics—2016 Update: A Report From the American Heart Association , 2016, Circulation.

[28]  R. Collins,et al.  Common variants at 30 loci contribute to polygenic dyslipidemia , 2009, Nature Genetics.

[29]  Alberto Piazza,et al.  Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants , 2009, Nature Genetics.

[30]  S. Snyder,et al.  An improved 2,4,6-trinitrobenzenesulfonic acid method for the determination of amines. , 1975, Analytical biochemistry.

[31]  Ralph Weissleder,et al.  Imaging the beating heart in the mouse using intravital microscopy techniques , 2015, Nature Protocols.

[32]  P. Herrero,et al.  Imaging of myocardial metabolism , 2005, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[33]  Ahmed Tawakol,et al.  Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography , 2005, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[34]  J. Rudd,et al.  PET imaging of inflammation in atherosclerosis , 2014, Nature Reviews Cardiology.