PET/MRI to study nanotherapy in atherosclerosis

PET/MRI 研究动脉粥样硬化的纳米疗法

基本信息

批准号：
8801993
负责人：
Willem Mulder
金额：
$ 58.27万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/8801993
关键词：
3-Dimensional Adverse effects Apolipoproteins Arterial Fatty Streak Atherosclerosis Autoradiography Biodistribution Blood Vessels Cardiovascular Diseases Caring Cause of Death Chronic Clinic Clinical Collaborations Combined Modality Therapy Coronary Arteriosclerosis Deposition Developed Countries Disease Dose Drug Formulations Drug Kinetics Environmental Risk Factor Evaluation Event Exhibits Extracellular Matrix FDA approved Goals 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 public health relevance quantitative imaging theranostics therapeutic target uptake

项目摘要

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）是西方世界的首要死因。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，实质性残留风险仍然很高。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目标。纳米医学通过改善治疗剂的药代动力学和生物分布，同时减少不良反应和不良相互作用，为治疗各种病理学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。由于纳米医学对于动脉粥样硬化的研究相对较少，因此需要开发新的成像策略来表征这种疾病，同时也允许纳米颗粒靶向和功效的定量可视化。在这个项目中，我们建议开发和利用 PET/MRI 技术对治疗动脉粥样硬化斑块炎症的纳米疗法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 (LNP) 和高密度脂蛋白 (HDL) 的 89Zr 放射性同位素标记方法。我们将在动脉粥样硬化兔模型中评估纳米报告技术。将应用广泛的离体成像和组织学技术来评估体内发现并揭示作用机制。具体目标是：目标 1：建立脂质体纳米颗粒的生物分布和斑块靶向性，其中只有一小部分用 89Zr 标记。定量评估 89Zr 标记 HDL 的斑块巨噬细胞靶向和生物分布。：通过 PET/MRI 来评估 89Zr 标记和载药 LNP 在动脉粥样硬化兔子中的疗效目标 2 目标 3。所有提议的纳米颗粒配方的各个成分和标记方法均已获得 FDA 批准，这一事实促进了向临床的转化。最后，使用纳米颗粒制剂快速抑制血管壁炎症并开发成像技术来监测其功效可能会对心血管疾病的治疗产生深远的影响。