Myocardial infarctions (MI) or heart attacks, ischemic strokes (IS) and peripheral artery disease (PAD), together considered cardiovascular disease (CVD), are all commonly caused by the same underlying pathology, atherosclerosis. MIs and ISs are the leading causes of death and disability worldwide. Atherosclerosis is a progressive pathology that develops asymptomatically over the course of many years as inflammatory plaques in the walls of arteries. Eventual ruptures of atherosclerotic plaques result in blood clots, blocking blood flow and causing infarctions (i.e. CVD events). Inflammatory plaques that are most likely to rupture are currently challenging to detect and characterize without invasive procedures. Currently available non-invasive imaging modalities for atherosclerosis lack sensitivity and/or specificity for inflammatory plaques. There is great need for a non-invasive imaging modality that can specifically detect inflammatory atherosclerotic plaques with high sensitivity. Such an imaging modality would enable more accurate identification of individuals at high risk for experiencing a first major CVD event (MI or IS) and would facilitate monitoring of atherosclerosis directed therapies and life-style modification. Achieving these benefits would meaningfully reduce the catastrophic toll that is inflicted upon our society by atherosclerosis mediated CVD events. To address this unmet need, Navidea and the University of Alabama Birmingham (UAB) are collaborating to develop Gallium-68 (68Ga) labelled tilmanocept as a radiopharmaceutical positron emission tomography (PET) imaging agent for inflammatory atherosclerotic plaques. Tilmanocept is a synthetic ligand for the macrophage mannose receptor (CD206) with â5 DTPA moieties that enable labeling with 68Ga. CD206+ macrophages are highly numerous in inflammatory plaques but not in plaques with resolved inflammation or uninvolved relevant tissue. The hypothesis of this proposal is that intravenously (IV) injected 68Ga-tilmanocept will localizes specifically to inflammatory plaques and permit sensitive quantitative imaging with PET. To test this hypothesis, we propose to evaluate 68Ga-tilmanocept PET imaging in the ApoE mouse model of atherosclerosis. Including appropriate controls, a total of 25 mice will be evaluated. In this model, inflammatory atherosclerotic plaques develop along the aortas of the mice. Animals will be injected IV with 68Ga-tilmanocept and imaged to quantitatively determine sites of 68Ga-tilmanocept localization. The animals will then be euthanized after which their aortas will be dissected and subjected to autoradiography. Areas of varying degrees of localization will be identified and processed for immunoflorescent (IF) evaluation with anti-CD206 antibodies and the murine macrophage marker F4/80. Quantitative assessments of CD206 and F4/80 expression will be compared to each other and to the degree of 68Ga-tilmanocept localization as determined by PET and autoradiography. These comparisons with determine the correlation between CD206 expression and 68Ga-tilmanocept localization and will confirm that CD206 expression is largely restricted to macrophages in inflammatory plaques. These experiments will establish the feasibility of 68Ga-tilmanocept based PET imaging to specifically identify inflammatory plaques and provide the foundation for further studies developing 68Ga-tilmanocept PET as a non-invasive atherosclerosis imaging modality in human subjects.
Public Health Relevance Statement: This project seeks to develop a gallium-68 (68Ga) labeled radiopharmaceutical diagnostic imaging agent, 68Ga-tilmanocept, for positron emission tomography (PET) imaging of atherosclerotic plaques in the walls of arteries and characterization of their inflammatory microenvironments. This project will enable improved risk assessment and monitoring of therapies for individuals at risk for myocardial infarctions (heart attacks) and ischemic strokes, the leading causes of death worldwide. If successful, this project will significantly reduce the catastrophic burdens inflicted upon our society by these conditions.
Project Terms: Address; Alabama; Angiography; Animals; Antibodies; Aorta; Apolipoprotein E; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; atherosclerotic plaque rupture; Autoradiography; base; Blood coagulation; Blood flow; calcification; Calcium; Cancer Patient; cancer surgery; Cardiac; Cardiovascular Diseases; cardiovascular disorder risk; Catheters; Cause of Death; Cells; Characteristics; Chronic; Data; Deposition; Development; Development Plans; Diagnostic Imaging; disability; Early Intervention; Embolism; Evaluation; Event; experience; experimental study; FDA approved; fluorodeoxyglucose; Foundations; Gallium; Goals; high risk; human subject; Image; imaging agent; imaging modality; Immune; Immunohistochemistry; improved; Individual; Infarction; Inflammation; Inflammatory; Intravenous; Ischemic Stroke; Label; Life; Life Style Modification; Ligands; Lipids; Location; macrophage; Magnetic Resonance Imaging; mannose receptor; Mediating; Modeling; Monitor; mouse model; Mus; Myocardial Infarction; Near-Infrared Spectroscopy; Necrosis; non-invasive imaging; Optical Coherence Tomography; Pathology; Patients; Pentetic Acid; Peripheral arterial disease; Persons; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Pre-Clinical Model; prevent; Procedures; Process; quantitative imaging; Radiolabeled; Radiopharmaceuticals; Resolution; Risk; Risk Assessment; Rupture; Sentinel Lymph Node; Serious Adverse Event; single photon emission computed tomography; Site; Small Business Technology Transfer Research; Societies; Specificity; Structure; Syndrome; targeted imaging; Technetium 99m; Techniques; Technology Assessment; Testing; Thinness; Time; Tissues; Ultrasonography; Universities; uptak
