Imaging of atheroma macrophage activities by rational liposomal shell design

描述（由申请人提供）：测量动脉粥样硬化中炎症活动的成像技术可能导致更好地表征斑块易损性并改变临床管理。该提案的目标集中于脂质体壳的合理设计，其与巨噬细胞相互作用以有效递送放射性造影剂，从而在动脉壁中保留足够的放射性造影剂以进行CT成像和定量。该建议侧重于两种不同的放射性造影剂负载的脂质体制剂。一种制剂由脂质体壳中的磷脂酰丝氨酸（PS）组成，所得脂质体类似于衰老细胞。另一种将氧化磷脂1-棕榈酰-2-（5-氧代戊酰）磷脂酰胆碱（POVPC）掺入脂质体壳中，所得脂质体模仿氧化低密度脂蛋白的外观。PS和POVPC都可以与巨噬细胞中的清道夫受体和CD 36相互作用，导致脂质体的吞噬作用。该提案的创新之处在于引入了特异性靶向巨噬细胞的磷脂物质，而不使用潜在的免疫原性抗体或使用颗粒材料，如氧化铁或被巨噬细胞非特异性摄取的带负电荷的脂质体。本提案中的另一个重要考虑因素是在更大的动物模型中测试这种成像策略：Watanabe遗传性高血压兔。这种动物模型不仅会产生类似人类的动脉粥样硬化，而且它是在临床计算机断层扫描（CT）扫描仪中更好地评估这种成像策略的理想尺寸，将来可以在人类受试者中进行测试。最后的考虑是使用成像模式，CT扫描，它提供了优越的上级空间分辨率，是一种公认的用于诊断人类狭窄冠状动脉病变的成像模式。通过CT成像测量非钙化斑块中炎症活动的能力将提供超出仅通过CT冠状动脉造影术评价狭窄病变的增量信息。因此，本建议旨在设计一种成像系统，可以很容易地采用进一步的研究在人类。如果成功，这将补充现有的成像技术，并允许更好地表征冠状动脉病变和患者管理。 公共卫生相关性：动脉粥样硬化性心血管疾病是一种缓慢进展的疾病，发展多年。动脉粥样硬化中的炎症和巨噬细胞活化在动脉粥样硬化的不稳定中起重要作用，导致斑块破裂和动脉闭塞。本申请旨在开发靶向巨噬细胞的新型放射性造影剂负载脂质体，以更好地检测和预测动脉粥样硬化的未来事件。

DESCRIPTION (provided by applicant): 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 complement existing imaging technologies and allow better characterization of coronary lesions and patient management. PUBLIC HEALTH RELEVANCE: 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.