It is well recognized that despite advances in cardiovascular care, the prevalence of atherosclerosis and its complications, myocardial infarction and stroke, remains the leading cause of morbidity and mortality worldwide. Current noninvasive methods to evaluate the status and assess the effects of therapeutic intervention rely mainly on anatomic and structural features of the lesion. New noninvasive molecular imaging techniques of atherosclerosis1 may enable a novel biologically based approach that exceeds anatomic and morphologic examination of the vessel wall. Current imaging modalities disclose minimal information about this key biological process. Thus, by characterizing the pathophysiological processes responsible for plaque progression and instability using non-invasive and reliable imaging approaches, it may be possible to early identify high-risk patients and to evaluate the effects of interventions, including emerging therapies. The central goal of this work is therefore the study of molecular imaging methods for the non-invasive evaluation of the biological activity associated with atherogenesis. We propose the use of versatile/modular (allowing facile interchange of MR imaging labels and ligands) and well-characterized high-density lipoprotein (HDL) imaging nanocarrier platforms for the targeted (known and newly discovered targets) study of the progression and regression of atherosclerotic plaques in vivo. These spherical HDL platforms will be programmed for single modality imaging (Gd-MR or iron oxide-MR) allowing assessment at possibly different levels of sensitivity (Aim 1). Based on in vivo efficacy imaging studies the lead candidate between the native and synthetic MR-HDL platforms will be selected for further study in the subsequent aims. In vitro and in vivo studies will be linked intimately with the nanocarriers design strategies and assembly work to achieve validation of the biological performance and mechanism of action elucidation of the HDL MR imaging platforms (Aim 2). Known and newly identified targets will be functionalized to achieve plaque specific selective targeting. We will demonstrate the in vivo efficacy of these targeted HDL MR-nanocarriers for the evaluation of plaque progression and regression in mouse and rabbit models of atherosclerosis (Aim 3).
Impact: Cardiovascular disease is the main killer worldwide, a pandemic largely driven by the growing prevalence of atherosclerosis. However, atherosclerosis progresses slowly and silently over decades, a prolonged course that represents a window of opportunity for diagnosis before symptoms occur. Thus, novel imaging techniques offer new prospects to detect early stages and identify those individuals with higher risk.
|Ramos-Cabrer, Pedro; Fay, Francois; Sanchez-Gaytan, Brenda L et al. (2016) Conformational Changes in High-Density Lipoprotein Nanoparticles Induced by High Payloads of Paramagnetic Lipids. ACS Omega 1:470-475|
|Fisher, Edward A (2016) Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back. Arterioscler Thromb Vasc Biol 36:226-35|
|Tang, Jun; Baxter, Samantha; Menon, Arjun et al. (2016) Immune cell screening of a nanoparticle library improves atherosclerosis therapy. Proc Natl Acad Sci U S A 113:E6731-E6740|
|Calcagno, Claudia; Fayad, Zahi A (2016) Imaging the Permeable Endothelium: Predicting Plaque Rupture in Atherosclerotic Rabbits. Circ Cardiovasc Imaging 9:|
|Calcagno, Claudia; Mulder, Willem J M; Nahrendorf, Matthias et al. (2016) Systems Biology and Noninvasive Imaging of Atherosclerosis. Arterioscler Thromb Vasc Biol 36:e1-8|
|Dweck, Marc R; Williams, Michelle C; Moss, Alastair J et al. (2016) Computed Tomography and CardiacÂ Magnetic Resonance in IschemicÂ HeartÂ Disease. J Am Coll Cardiol 68:2201-2216|
|Zhao, Yiming; Fay, FranÃ§ois; Hak, Sjoerd et al. (2016) Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy. Nat Commun 7:11221|
|Calcagno, Claudia; Lobatto, Mark E; Dyvorne, Hadrien et al. (2015) Three-dimensional dynamic contrast-enhanced MRI for the accurate, extensive quantification of microvascular permeability in atherosclerotic plaques. NMR Biomed 28:1304-14|
|Lobatto, Mark E; Calcagno, Claudia; Millon, Antoine et al. (2015) Atherosclerotic plaque targeting mechanism of long-circulating nanoparticles established by multimodal imaging. ACS Nano 9:1837-47|
|van der Valk, Fleur M; van Wijk, Diederik F; Lobatto, Mark E et al. (2015) Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration. Nanomedicine 11:1039-46|
Showing the most recent 10 out of 71 publications