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Anti-inflammatory nanoparticle formulations to treat atherosclerosis

治疗动脉粥样硬化的抗炎纳米颗粒制剂

基本信息

批准号：
9279233
负责人：
Willem Mulder
金额：
$ 58.97万
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：
2014-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279233
关键词：
Adverse effects Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biodistribution Biological Biological Assay Biological Availability Blood CNR1 gene CNR2 gene Cannabinoids Cardiovascular system Cause of Death Cell Line Cells Clinic Clinical Coronary Coronary Arteriosclerosis Development Dose Drug Delivery Systems Drug Formulations Event Extracellular Matrix FDA approved Flow Cytometry Formulation Generations Goals Half-Life High Density Lipoprotein therapy High Density Lipoproteins Histologic Histological Techniques Histology Human Hydrophobicity Image Image Cytometry Imagery Imaging Techniques Immunohistochemistry In Vitro Individual Inflammation Inflammatory Knockout Mice Label Lesion Libraries Ligation Lipids Lipoproteins Magnetic Resonance Imaging Messenger RNA Microfluidics Molecular Monitor Mus Myocardial Infarction Near-infrared optical imaging Oral Peptide Hydrolases Pharmaceutical Preparations Pharmacology Prevention strategy Property Protocols documentation Recurrence Regimen Residual state Risk Risk Factors Rupture Specificity Stroke Techniques Testing Tetrahydrocannabinol Therapeutic Therapeutic Studies Tissues Translations Treatment Efficacy Treatment Protocols Western World Work base cannabinoid treatment cell type controlled release drug development efficacy study fluorescence molecular tomography human disease in vitro testing in vivo in vivo imaging lipophilicity macrophage monocyte mouse model nanoparticle nanotherapy non-invasive imaging novel public health relevance therapeutic target tool

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. Statins have known pleiotropic anti-inflammatory effects, but to exploit and amplify these effects, novel formulations that effectively target plaques and accumulate the drug at high concentration in target tissue need to be developed. Similarly to statins, cannabinoids, a class of hydrophobic compounds that can activate either the cannabinoid receptor 1 (CB1) or CB2 receptor, have shown potent anti-inflammatory properties as well. To better exploit both drug classes in the context of atherosclerotic disease, nanoparticle formulations offer significant advantages, including the reduction of systemic or psychotropic effects, while simultaneously increasing the efficacy and bioavailability through local atherosclerotic plaque drug delivery. In this context, lipoprotein nanoparticles may be excellently suited as they can carry payloads of lipophilic drugs and naturally target atherosclerotic plaque macrophages. The aforementioned nanoparticle platforms will be produced using microfluidics. Full in vitro targeting and efficacy studies will b performed. In vivo, biodistribution and imaging-assisted therapeutic studies will be performed on a traditional mouse model of atherosclerosis as well as an myocardial infarction aggravated mouse model of atherosclerosis. Extensive immunofluorescent, histological, and molecular biological techniques will be applied to evaluate the in vivo findings and to unravel the mechanism of action. The specific aims are: Aim 1: To create a library of drug-loaded lipoprotein nanoparticles using microfluidics. Aim 2: To study the biodistribution and plaque targeting of these lipoprotein nanoparticles in atherosclerotic ApoE-KO mice via imaging. Aim 3: To conduct a HDL nanotherapy study in atherosclerotic ApoE-KO mice. Aim 4: To conduct a HDL therapy study in mice with MI-aggravated atherosclerosis. Translation to the clinic is facilitated by the fact that the individual components of all the proposed nanoparticle formulations are FDA approved. Finally, the paradigm shift, i.e. using nanoparticle formulations to alter the pharmacological effects of two well-known drug classes could have a broad and profound impacts on the management of different human 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。目前的预防策略集中在控制危险因素和血脂水平。即使完全达到治疗目标，实质性剩余风险仍然很高。在人类中，浸润斑块的单核细胞分化成炎性巨噬细胞，产生蛋白水解酶，消化细胞外基质，导致斑块破裂。因此，斑块炎症被作为降低动脉粥样硬化血栓事件复发率的治疗靶点。他汀类药物具有已知的多效性抗炎作用，但是为了利用和放大这些作用，需要开发新的制剂，需要开发有效靶向斑块并在靶组织中以高浓度积累药物的方法。与他汀类药物类似，大麻素是一类可以激活大麻素受体1（CB 1）或CB 2受体的疏水化合物，也显示出有效的抗炎特性。为了在动脉粥样硬化疾病的背景下更好地利用这两种药物类别，纳米颗粒制剂提供了显著的优势，包括减少全身或精神作用，同时通过局部动脉粥样硬化斑块药物递送增加疗效和生物利用度。在这种情况下，脂蛋白纳米颗粒可能非常适合，因为它们可以携带亲脂性药物的有效载荷并天然靶向动脉粥样硬化斑块巨噬细胞。上述纳米颗粒平台将使用微流体技术生产。将进行完整的体外靶向和疗效研究B。将对动脉粥样硬化的传统小鼠模型以及动脉粥样硬化的心肌梗死加重小鼠模型进行体内生物分布和成像辅助治疗研究。广泛的免疫荧光，组织学和分子生物学技术将被应用于评估在体内的结果，并解开的作用机制。具体目标是：目标1：使用微流体技术创建载药脂蛋白纳米颗粒库。目的2：通过影像学研究这些脂蛋白纳米粒在动脉粥样硬化ApoE-KO小鼠体内的生物分布和斑块靶向性。目的3：在动脉粥样硬化ApoE-KO小鼠中进行HDL纳米治疗研究。目的4：在MI加重的动脉粥样硬化小鼠中进行HDL治疗研究。所有提出的纳米颗粒制剂的单个组分都是FDA批准的，这一事实促进了向临床的转化。最后，范式转变，即使用纳米颗粒制剂来改变两种众所周知的药物类别的药理作用，可能对不同人类疾病的管理产生广泛而深远的影响。