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Atherosclerosis

We have a large effort devoted to imaging inflammation in atherosclerosis, part of the Donald W. Reynolds Cardiovascular Clinical Research Center at Harvard Medical School. Our laboratory has previously designed protease-activatable NIRF imaging agents (Weissleder et al Nature Biotechnology 1999) as well as macrophage-targeted superparamagnetic iron oxide agents for MRI (Harsinghani et al NEJM 2003). We are actively developing these first generation agents to image various aspects of inflammation, including protease activity, endothelial cell activation, activated macrophages, and leukocyte trafficking. The initial efforts in this lab demonstrated that a cathepsin B activatable NIRF agent could identify inflammatory atherosclerosis in vivo and potentially serve as a new biomarker for vulnerable plaque (Chen et al Circulation 2002). Validation of the new agents is ongoing in murine models of atherosclerosis and as well as on other gene deletion (knockout) mice. We believe that these imaging agents will be equally promising for imaging inflammation in human atherosclerosis, and are actively testing these agents to image inflammation in human carotid endarterectomy specimens. In addition to providing further insight into atherosclerosis biology, these agents could aid in the clinical diagnosis of high-risk atherosclerotic lesions and/or high-risk patients.

Thrombosis

Acutely formed thrombi are the causal agent in life-threatening clinical syndromes such as myocardial infarction, stroke, and pulmonary embolism. CMIP is actively involved in developing and validating the molecular imaging technology to assay important molecules in acute thrombosis. Thus far, we have investigated a new protease-activatable NIRF agent to study thrombin enzyme activity in vivo (Jaffer et al ATVB 2002). Thrombin, a serine protease that is responsible for fibrin generation, is an active target of a number of clinical antithrombotic therapies. We demonstrated that thrombin activity can be imaged with high resolution intravital fluorescence microscopy in a murine model of femoral thrombosis. This work has contributed to the understanding the temporal activity of thrombin in acute and subacute thrombi, and has provided a new method to image biologically acute thrombi.
In another investigation, we developed and investigated a new NIRF molecular imaging agent that assays activated factor XIII (FXIIIa) activity in vivo (Jaffer et al Circulation 2004). FXIIIa is an acutely expressed, thrombin-activated transglutaminase that is responsible for crosslinking fibrin and plasmin inhibitors, with the consequence of making thrombi resistant to fibrinolytic therapy. We developed a NIR fluorescent FXIIIa peptide substrate, derived from the amino terminus of alpha-2-antiplasmin, a natural substrate for FXIIIa. The report demonstrated marked signal enhancement of thrombi in vivo with this agent, and also showed that the agent was covalently crosslinked to fibrin. We are now involved with translating this agent into larger animal systems, with the aim of detecting FXIIIa-enhanced thrombi in vivo using CMIR-built intravascular NIRF catheters that could eventually be used in human coronary arteries in vivo. This work has further contributed to understanding the role of FXIIIa in acute thrombi, and provided a new imaging method to detect biologically acute thrombi.

Myocardial Injury and Inflammation

Despite significant advances in the understanding and treatment of heart failure, the condition remains a major public health problem in the United States. The aim of our group is therefore to apply molecular imaging techniques to better understand the pathophysiology of myocardial injury, and to use these imaging techniques to assess the potential of novel cardioprotective strategies. We are particularly interested in the imaging of cardiomyocyte apoptosis and myocardial inflammation in both acute and chronic myocardial injury.
Cardiomyocyte apoptosis has been implicated in a broad range of cardiovascular diseases including ischemia, reperfusion injury and heart failure. We have developed a novel magneto-optical nanoparticle, AnxCLIO-Cy5.5, in our laboratory that allows apoptotic cells to be imaged with both near infrared fluorescence (NIRF) and magnetic resonance imaging techniques (Bioconjugate Chemistry, 2004). We have shown that AnxCLIO-Cy5.5 has a similar affinity for apoptotic cells to that of the highly established annexin V-FITC probe, and we have validated the ability of AnxCLIO-Cy5.5 to detect cardiomyocyte apoptosis in-vitro and, in-vivo, in a murine model of ischemia-reperfusion injury.
Much of our work with AnxCLIO-Cy5.5 involves the acquisition of cine cardiac MR images in live mice in order to correlate the magnetic readout from the nanoparticle probe with both segmental and global indices of myocardial function. We believe that this platform constitutes a powerful model for the study of myocardial disease, and has the potential to provide novel insights in to the biology and treatment of heart failure.