Integrated drug-in-cell therapy of in-stent restenosis

支架内再狭窄的综合药物细胞治疗

基本信息

批准号：
9256528
负责人：
Michael Chorny
金额：
$ 25.2万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256528
关键词：
Acute Address Adverse effects Affect Angioplasty Animals Arterial Injury Arteries Atherosclerosis Benzoates Biological Assay Blood Vessels Carotid Atherosclerotic Disease Carotid stent Cell Therapy Cells Chronic Clinical Clinical Trials Coculture Techniques Control Animal Development Disease Dose Drug Targeting Drug or chemical Tissue Distribution Effectiveness Encapsulated Endothelial Cells Endothelium Estradiol Estradiol Benzoate Estrogens Evaluation Event Exhibits Functional disorder Generalized Atherosclerosis Genes Growth Iatrogenesis Image Analysis Incidence Injury Intervention Kinetics Lesion Life Magnetic nanoparticles Magnetism Mechanics Mediating Metals Methods Modality Modeling Modification Molecular NOS3 gene Natural regeneration Nitric Oxide Nitric Oxide Synthase Obstruction Outcome Pathway interactions Patient risk Patients Performance Pharmaceutical Preparations Pharmacology Procedures Process Production Property Rattus Recovery Reporting Safety Smooth Muscle Myocytes Source Stenosis Stents Techniques Treatment Efficacy Vascular Diseases antiproliferative agents base bioluminescence imaging cardiovascular risk factor cell injury computerized effective therapy efficacy study experimental study gene therapy healing human disease implantation magnetite ferrosoferric oxide morphometry nanocarrier nanoparticle novel novel therapeutics particle poly(lactide)prevent protective effect public health relevance repaired restenosis targeted delivery uptake vector

项目摘要

DESCRIPTION (provided by applicant): Injury-triggered renarrowing (restenosis) of arteries treated with angioplasty to relieve atherosclerotic obstruction remains a challenge due to a lack of therapies combining adequate efficacy and safety. Strategies aimed at accelerated vascular healing and endothelium regeneration have potential to prevent restenosis while avoiding the side effects of the currently used therapies. However, in order to realize this potential a significant improvement in their efficiency is required. This proposal is concerned with an integrated drug-in-cell antirestenotic strategy based on dual functionalization of endothelial cell with drug-loaded magnetic nanocarriers to provide them with capacity for stent-targeted delivery and enhanced antirestenotic effectiveness. The latter is achieved by inducing and activating endothelial nitric oxide synthase with estradiol formulated in magnetic nanoparticles (MNP) in the form of its precursor, estradiol benzoate (E2Bz). The present studies will establish feasibilit of using this approach for preventing in-stent restenosis and achieving facilitated reendothelialization in a validated rat model of atherosclerosis reproducing key features of human disease .The following specific aims will be addressed: AIM 1: Drug-in-cell approach evaluation and optimization in culture and co-culture studies. E2Bz-loaded biodegradable MNP will be formulated, and their size, composition, magnetic properties and drug release profile will be characterized. Cell compatibility, internalization and degradation kinetics of MNP, as well as E2Bz-induced nitric oxide synthesis by MNP-functionalized endothelial cells and its growth inhibitory effect on co-cultured smooth muscle cells will be the main endpoints of the Aim 1 experiments. AIM 2: Targeting, reendothelialization and efficacy studies. Arterial localization, tissue distribution and endothelium recovery after magnetically targeted delivery of functionalized cells will be studied in the rat atherosclerosis/ carotid stenting model. The extent of restenosis will be determined two weeks post-delivery by computerized morphometry, and the pharmacological effect of cell functionalization will be delineated using animals treated with cells loaded with blank MNP as controls.

描述（由适用提供）：用血管成形术治疗的动脉造成的损伤触发的重骨（再狭窄）缓解动脉粥样硬化的异议仍然是一个挑战，这是由于缺乏结合足够有效性和安全性的治疗方法。旨在加速血管愈合和预硫代植物再生的策略具有预防再狭窄的潜力，同时避免了当前使用的疗法的副作用。但是，为了实现这一潜力，需要显着提高其效率。该提案与基于用药物负载的磁性纳米载体对内皮细胞的双重功能化的综合药物抗抗菌病策略有关，以为他们提供靶向靶向的递送和增强的抗抗菌病效能的能力。后者是通过在磁性纳米颗粒（MNP）中以其前体雌二醇苯甲酸酯（E2Bz）形式激活的和激活内皮一氧化氮合酶来实现的。本研究将确定使用这种方法来预防固定的再狭窄，并在经过验证的大鼠动脉粥样硬化模型中重现人类疾病关键特征的验证的重生皮层化。将制定负载E2BZ的可生物降解MNP，并将表征它们的大小，组成，磁性和药物释放曲线。 MNP的细胞兼容性，内在化和降解动力学以及E2Bz诱导的MNP官能化内皮细胞的一氧化氮合成及其对共培养平滑肌细胞的生长抑制作用是AIM 1实验的主要端口。目标2：靶向，再去性皮化和有效的研究。在大鼠动脉粥样硬化/颈动脉支架支架模型中，磁性靶向细胞递送后，动脉定位，组织分布和内皮恢复将是研究的。程度通过计算机化形态计量学后两周将确定再狭窄的病，并使用装有空白MNP作为对照的细胞处理的动物来划定细胞功能化的药物作用。