Imaging of atheroma macrophage activities by rational liposomal shell design

摘要 测量动脉粥样硬化炎症活动的成像技术可能会导致更好的 斑块易损性的特征和改变临床治疗。这项提案的目标集中在 合理设计与巨噬细胞相互作用的脂质体外壳，以有效传递放射造影剂， 从而在动脉壁保留足够的放射造影剂以供CT成像和定量。这项建议 重点介绍了两种不同的放射造影剂脂质体配方。一种制剂包括 脂质体外壳中的磷脂酰丝氨酸(PS)，生成的脂质体类似于衰老细胞。另一个 将氧化的磷脂1-棕榈酰基-2-(5-氧代戊基)磷脂酰胆碱(POVPC)加入到 脂质体壳及其生成的脂质体模仿氧化低密度脂蛋白的外观。两者都有 PS和POVPC可与巨噬细胞清道夫受体和CD36相互作用，导致巨噬细胞吞噬 脂质体。这项建议的创新之处在于加入了磷脂物种，特别是 靶向巨噬细胞，而不使用潜在的免疫原性抗体或使用诸如 作为氧化铁或带负电荷的脂质体，非特异性地被巨噬细胞摄取。另一个 这项建议中的重要考虑因素是在更大的动物模型中测试这种成像策略： 渡边遗传性高脂血症兔。这个动物模型不仅形成了类似人类的动脉粥样硬化， 它是在临床计算机断层(CT)扫描仪中更好地评估这种成像策略的理想尺寸 将来可以在人体受试者身上进行测试。最后考虑的是成像模式的使用， CT扫描，提供卓越的空间分辨率，是诊断狭窄的公认成像方式 人类的冠状动脉病变。CT测量非钙化斑块炎症活动的能力 成像将提供超越CT冠状动脉狭窄病变评估的增量信息 光是血管造影术。因此，该提案旨在设计一种可以容易地用于 在人类身上的进一步研究。如果成功，这将补充现有的成像技术，并允许更好地 冠状动脉病变的特征和患者管理。

ABSTRACT 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.