Imaging of atheroma macrophage activities by rational liposomal shell design

描述(由申请人提供)：测量动脉粥样硬化炎症活动的成像技术可能导致更好地表征斑块脆弱性并改变临床治疗。这项建议的目标是合理设计与巨噬细胞相互作用的脂质体外壳，以有效地传递放射造影剂，从而在动脉壁中保留足够的放射造影剂用于CT成像和定量。这项建议侧重于两种不同的放射造影剂脂质体配方。一种制剂由脂质体外壳中的磷脂酰丝氨酸(PS)组成，生成的脂质体类似于衰老细胞。另一种是将氧化的磷脂1-棕榈酰基-2-(5-氧代戊基)磷脂酰胆碱(POVPC)结合到脂质体外壳中，得到的脂质体模仿氧化的低密度脂蛋白的外观。PS和POVPC都能与巨噬细胞的清道夫受体和CD36相互作用，导致脂质体的吞噬作用。这一建议的创新之处在于加入了专门针对巨噬细胞的磷脂物种，而不使用潜在的免疫原性抗体，也不使用颗粒材料，如氧化铁或非特异性地被巨噬细胞摄取的带负电荷的脂质体。这项建议的另一个重要考虑是在一个更大的动物模型：渡边遗传性高脂血症兔身上测试这种成像策略。这种动物模型不仅形成了类似人类的动脉粥样硬化，而且是在临床计算机断层扫描(CT)扫描仪中更好地评估这一成像策略的理想尺寸，将来可以在人类受试者身上进行测试。最后的考虑是使用一种成像方式，CT扫描，它提供了优越的空间分辨率，是一种被接受的诊断人类冠状动脉狭窄病变的成像方式。使用CT成像测量非钙化斑块中的炎症活动的能力将提供比仅通过CT冠状动脉造影评估狭窄病变更多的信息。因此，这项提议旨在设计一种易于在人体上进行进一步研究的成像系统。如果成功，这将补充现有的成像技术，并允许更好地描述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多年来进展缓慢的疾病。炎症和巨噬细胞活化在动脉粥样硬化的失稳中起重要作用，导致斑块破裂和动脉闭塞。这一应用寻求开发新型的以巨噬细胞为靶点的放射对比剂脂质体，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.