Imaging of atheroma macrophage activities by rational liposomal shell design

通过合理的脂质体壳设计对动脉粥样硬化巨噬细胞活性进行成像

• 批准号: 8410531
• 负责人: Patrick Kee
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-09 至 2014-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410531
• 关键词: Adopted; Animal Model; Animals; Antibodies; Appearance; Arterial Fatty Streak; Atherosclerosis; Blood Circulation; CD36 gene; Cells; Characteristics; Charge; Clinical; Clinical Management; Contrast Media; Coronary; Coronary Angiography; Coronary artery; Detection; Diagnosis; Disease Progression; Disease regression; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Ensure; Evaluation; Event; Future; Goals; Homing; Human; Image; Image Analysis; Imaging Techniques; Imaging technology; In Vitro; Inflammation; Inflammatory; Inherited; Lead; Lecithin; Lesion; Ligands; Lipids; Liposomes; Macrophage Activation; Measures; Modification; Monitor; Oryctolagus cuniculus; Particulate; Patients; Phagocytosis; Phosphatidylserines; Phospholipids; Play; Preparation; Property; Resolution; Reticuloendothelial System; Role; Rupture; Scanning; Surface; System; Techniques; Testing; Toxic effect; Tracer; X-Ray Computed Tomography; artery occlusion; base; biomaterial compatibility; clinical application; design; high risk; human subject; imaging modality; immunogenic; improved; in vivo; innovation; iron oxide; macrophage; molecular imaging; novel; oxidized low density lipoprotein; scavenger receptor; senescence; uptake

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.

摘要 测量动脉粥样硬化中炎症活动的成像技术可能会更好地 表征斑块脆弱性和改变临床管理。本提案的目标是 与巨噬细胞相互作用以有效递送放射性造影剂的脂质体壳的合理设计， 导致在动脉壁中保留足够的放射性造影剂用于CT成像和定量。这项建议 集中于两种不同的放射造影剂负载的脂质体制剂。一种制剂包括 磷脂酰丝氨酸（PS）的脂质体壳与所得脂质体类似衰老细胞。另 将氧化磷脂，1-棕榈酰-2-（5-氧戊酰）磷脂酰胆碱（POVPC）， 脂质体壳，所得脂质体模仿氧化低密度脂蛋白的外观。两 PS和POVPC可以与巨噬细胞中的清道夫受体和CD 36相互作用，导致吞噬 脂质体。该提案的创新之处在于引入了磷脂物质， 靶向巨噬细胞，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吸收的带负电荷的脂质体。另 该提议中的重要考虑是在较大的动物模型中测试该成像策略： 渡边遗传性高脂血症兔。这种动物模型不仅会产生类似人类的动脉粥样硬化， 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 将来可以在人类身上进行测试。最后考虑的是使用成像模式， CT扫描，提供上级空间分辨率，是诊断狭窄的公认成像方式 冠状动脉病变。CT测量非钙化斑块中炎症活动的能力 除了CT冠状动脉成像评价狭窄病变外， 只有血管造影。因此，该提议旨在设计一种成像系统，其可以容易地被采用用于 在人类中的进一步研究。如果成功，这将补充现有的成像技术， 冠状动脉病变的表征和患者管理。