Imaging techniques that measure the inflammatory activities in the atheroma may lead to better characterization of plaque vulnerability and alter clinical management. The goal of this proposal focuses on rational designs of the liposomal shell that interact with macrophages for efficient delivery of radiocontrast, leading to retention of sufficient radiocontrast in the arterial wall for CT imaging and quantitation. This proposal focuses on two different radiocontrast-loaded liposomal formulations. One preparation consists of phosphatidylserine (PS) in the liposomal shell with resultant liposomes resembling senescent cells. The other incorporates oxidized phospholipids, 1-palmitoyl-2-(5-oxovaleryl) phosphatidylcholine (POVPC), into the liposomal shell with resultant liposomes mimicking the appearance of oxidized low density lipoproteins. Both PS and POVPC can interact with scavenger receptors and CD36 in macrophages, leading to phagocytosis of the liposomes. The innovation in this proposal is the incorporation of phospholipid species that specifically targets macrophages without using potentially immunogenic antibodies or the use of particulate materials such as iron oxide or negatively-charged liposomes that are taken up non-specifically by macrophages. The other important consideration in this proposal is the testing of this imaging strategy in a larger animal model: Watanabe Hereditary Hyperlipidemic rabbits. Not only does this animal model develops human-like atheroma, it is the ideal size for better evaluation of this imaging strategy in a clinical computed tomographic (CT) scanner that can be tested in human subjects in the future. The final consideration is the use of an imaging modality, CT scanning, that offers superior spatial resolution and is an accepted imaging modality for diagnosing stenotic coronary lesions in humans. The ability to measure the inflammatory activities in non-calcified plaques with CT imaging will provide incremental information beyond the evaluation of stenotic lesions by CT coronary angiography alone. Thus, this proposal aims to design an imaging system that can be readily adopted for further studies in humans. If successful, this will compliment existing imaging technologies and allow better characterization of coronary lesions and patient management.
Atherosclerotic cardiovascular disease is a slowly progressive condition that develops over years. Inflammation and macrophage activation in the atheroma plays an important role in the destabilization of atheroma, leading to plaque rupture and arterial occlusion. This application seeks to develop novel radiocontrast-loaded liposomes that target macrophages for better detection and prediction of future events in atherosclerosis.
|Kee, Patrick; Bagalkot, Vaishali; Johnson, Evan et al. (2015) Noninvasive detection of macrophages in atheroma using a radiocontrast-loaded phosphatidylserine-containing liposomal contrast agent for computed tomography. Mol Imaging Biol 17:328-36|