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: 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
• 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

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）是西方世界死亡的主要原因。目前，预防策略专注于控制危险因素和脂质水平。即使完全满足治疗目标，大量残留风险仍然很高。在人类中，浸润斑块分化成炎症性巨噬细胞的单核细胞会产生蛋白水解酶，从而消化细胞外基质，从而导致斑块破裂。因此，将牙菌斑炎症作为治疗靶标，以降低动脉粥样硬化事件的复发率。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希望的相互作用，从而为治疗多种病理提供了令人兴奋的新可能性。在动脉粥样硬化的领域，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提供潜在的革命性治疗方面。由于纳米医学对于动脉粥样硬化仍然相对尚未探索，因此需要开发纳米颗粒靶向和疗效的定量可视化，因此还允许这种疾病表征这种疾病。在这个项目中，我们建议开发和利用PET/MRI技术，以基于成像的纳米疗法评估动脉粥样硬化斑块炎症。为此，我们与纪念斯隆·凯特林癌症中心的放射性化学家合作，我们开发了89ZR放射性同位素标记方法的脂质体纳米颗粒（LNP）和高密度脂蛋白（HDL）。我们将在动脉粥样硬化的兔模型中评估纳米孢子技术。将应用广泛的体内成像和组织学技术来评估体内发现并揭示作用机理。具体目的是：目标1：建立脂质体纳米颗粒的生物分布和斑块靶向，其中只有一小部分用89zr标记。定量评估89ZR标记的HDL的斑块巨噬细胞靶向和生物分布。 ：疗法评估疗效目标2 AIM 2 AIM 3在PET/MRI中，在动脉粥样硬化的兔子中，在89ZR标记的LNP和药物的LNP中。通过以下事实，将所有提出的纳米颗粒制剂的各个组件和标记方法均获得FDA批准，从而促进了转化为诊所。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对心血管疾病的治疗产生深远的影响。