PET/MRI to study nanotherapy in atherosclerosis

PET/MRI 研究动脉粥样硬化的纳米疗法

• 批准号: 8962168
• 负责人: Willem Mulder
• 金额: $ 59.07万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-14 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962168
• 关键词: 3-Dimensional; Adverse effects; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Autoradiography; Biodistribution; Blood Vessels; Cardiovascular Diseases; Cause of Death; Chronic; Clinic; Clinical; Collaborations; Combined Modality Therapy; Coronary Arteriosclerosis; Deposition; Developed Countries; Disease; Dose; Drug Kinetics; Environmental Risk Factor; Evaluation; Event; Exhibits; Extracellular Matrix; FDA approved; Formulation; Goals; Health; High Density Lipoproteins; Histological Techniques; Human; Image; Imagery; Imaging Techniques; Imaging technology; Individual; Inflammation; Inflammatory; Insulin Resistance; Intravenous; LDL Cholesterol Lipoproteins; Label; Lipids; Liposomes; Magnetic Resonance Imaging; Memorial Sloan-Kettering Cancer Center; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Oral; Oryctolagus cuniculus; Pathology; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phospholipids; Positron-Emission Tomography; Predictive Value; Prevention strategy; Radioisotopes; Recurrence; Recurrent disease; Residual state; Risk; Risk Factors; Risk Reduction; Rupture; Specificity; Stroke; Systemic disease; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Translations; Western World; abdominal aorta; acute coronary syndrome; base; blood pressure regulation; contrast enhanced; cost; density; flexibility; imaging agent; imaging biomarker; improved; in vivo; infancy; macrophage; meetings; molecular imaging; monocyte; mortality; nanomedicine; nanoparticle; nanotherapy; neovascularization; novel; optical imaging; quantitative imaging; standard of care; theranostics; therapeutic target; uptake

DESCRIPTION (provided by applicant): Atherosclerosis and its major clinical manifestation, coronary artery disease (CAD), is the leading cause of death in the western world. Preventive strategies currently focus on controlling risk factors and lipid levels. Substantial residual risk remains high, even when treatment goals are fully met. In humans, monocytes that infiltrate the plaque differentiate into inflammatory macrophages produce proteolytic enzymes that digest extracellular matrix causing plaque rupture. Plaque inflammation is therefore pursued as a therapeutic target to lower the recurrent rates of atherothrombotic events. Nanomedicine offers exciting new possibilities for the treatment of a variety of pathologies by improving the pharmacokinetics and biodistribution of therapeutic agents, while simultaneously decreasing adverse effects and undesired interactions. In the field of atherosclerosis, nanomedicine is still in its infancy, but is expected to provide potentially revolutionary advances in treatment for the most challenging aspects of cardiovascular diseases. Since nanomedicine remains relatively unexplored for atherosclerosis, novel-imaging strategies that allow characterizing this disease, but also allow the quantitative visualization of nanoparticle targeting and efficacy need to be developed. In this project, we propose to develop and utilize PET/MRI technology for the imaging-based evaluation of nanotherapy for the treatment of atherosclerotic plaque inflammation. To that aim, in collaboration with radiochemists at Memorial Sloan Kettering Cancer Center, we have developed 89Zr radioisotope labeling methods for liposomal nanoparticles (LNPs) and high-density lipoprotein (HDL). We will evaluate the nanoreporter technology in a rabbit model of atherosclerosis. Extensive ex vivo imaging and histological techniques will be applied to evaluate the in vivo findings and to unravel the mechanism of action. The specific aims are: Aim 1: To establish the biodistribution and plaque targeting of liposomal nanoparticles of which only a small fraction is labeled with 89Zr. To quantitatively evaluate plaque macrophage targeting and biodistribution of 89Zr-labeled HDL. : To theranostically evaluate the efficacy Aim 2 Aim 3 of 89Zr-labeled and drug-loaded LNPs in atherosclerotic rabbits by PET/MRI. Translation to the clinic is facilitated by the fact that the individual components of all the proposed nanoparticle formulations and the labeling methods are FDA approved. Finally, using nanoparticle formulations to rapidly inhibit vessel wall inflammation and develop imaging technology to monitor their efficacy may have a profound impact on the management of cardiovascular diseases.

描述（由申请人提供）：动脉粥样硬化及其主要临床表现冠状动脉疾病（CAD）是西方世界的主要死亡原因。目前的预防策略侧重于控制危险因素和血脂水平。即使完全达到治疗目标，实质性的残余风险仍然很高。在人类中，浸润斑块的单核细胞分化为炎性巨噬细胞，产生蛋白水解酶，消化细胞外基质，导致斑块破裂。因此，斑块炎症被视为降低动脉粥样硬化血栓事件复发率的治疗靶点。纳米医学通过改善药物的药代动力学和生物分布，同时减少不良反应和不期望的相互作用，为治疗各种病理提供了令人兴奋的新可能性。在动脉粥样硬化领域，纳米医学仍处于起步阶段，但有望为心血管疾病最具挑战性的方面的治疗提供潜在的革命性进展。由于纳米医学在动脉粥样硬化方面的研究相对较少，因此需要开发新的成像策略，既可以表征这种疾病，又可以定量观察纳米颗粒的靶向性和疗效。在本项目中，我们建议开发和利用PET/MRI技术对纳米治疗动脉粥样硬化斑块炎症进行基于成像的评估。为此，我们与纪念斯隆凯特琳癌症中心的放射化学家合作，开发了用于脂质体纳米颗粒（LNPs）和高密度脂蛋白（HDL）的89Zr放射性同位素标记方法。我们将在兔子动脉粥样硬化模型中评估纳米报告技术。广泛的离体成像和组织学技术将应用于评估体内的发现和揭示作用机制。具体目的如下：目的1：建立脂质体纳米颗粒的生物分布和斑块靶向性，其中只有一小部分标有89Zr。定量评价89zr标记HDL在斑块巨噬细胞中的靶向性和生物分布。目的：应用PET/MRI技术评价89zr标记和载药LNPs对动脉粥样硬化家兔的疗效。所有提议的纳米颗粒配方的单个成分和标记方法都是FDA批准的，这一事实促进了对临床的转化。最后，利用纳米颗粒配方快速抑制血管壁炎症，并开发成像技术监测其疗效，可能对心血管疾病的管理产生深远的影响。