Nanoparticle MR Imaging of BBB Inflammation at High Tesla in CNS Tumors

CNS 肿瘤高特斯拉血脑屏障炎症的纳米颗粒 MR 成像

基本信息

批准号：
7341663
负责人：
EDWARD A. NEUWELT
金额：
$ 54.48万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-19 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341663
关键词：
Aftercare Anatomy Angiography Animal Model Animals Antigen-Presenting Cells Arts Astrocytes Biopsy Blood - brain barrier anatomy Blood Vessels Blood Volume Brain Neoplasms Cells Central Nervous System Lymphoma Central Nervous System Neoplasms Cerebrum Clinical Trials Contrast Media Data Dendritic Cells Diffusion Electron Microscopy Funding Gadolinium Glioblastoma Glioma Goals Health Sciences Histology Hour Human ITGAM gene Image Imagery Immigration In Vitro Inflammation Inflammatory Infusion procedures Injury Intravenous Intravenous Bolus Iron Label Lesion Leukocytes Localized Magnetic Resonance Magnetic Resonance Angiography Magnetic Resonance Imaging Magnetism Malignant Neoplasms Measurement Metastatic Neoplasm to the Central Nervous System Metastatic malignant neoplasm to brain Methods Modeling Molecular Molecular Weight Neoplasm Metastasis Neoplasms in Vascular Tissue Neuraxis Oregon Pathology Perfusion Peripheral Permeability Phagocytes Phase I Clinical Trials Phase II Clinical Trials Prior Chemotherapy Process Property Protamine Sulfate Protamines Protocols documentation Radiation Radiation therapy Rattus Research Research Personnel Resolution Safety Signal Transduction Specificity Standards of Weights and Measures Steroids Testing Therapeutic Time Toxic effect Universities Vascular Permeabilities antiangiogenesis therapy base bevacizumab cancer therapy cell type cellular imaging central nervous system injury chemotherapy day ferumoxides ferumoxtran ferumoxytol human subject improved in vivo iron oxide magnetic field nanoparticle neoplastic neoplastic cell neurovascular unit novel particle response restoration therapeutic angiogenesis trafficking trial comparing tumor tumor xenograft vascular inflammation

项目摘要

In this proposal we will test the overall hypothesis that high Tesla magnetic resonance (MR) imaging with magnetic iron oxide nanoparticles will add quantitative perfusion data and cell specific imaging of the neurovascular unit to classic anatomic MR of central nervous system (CMS)metastases and glioblastoma. We propose to test three major hypotheses: A) The nanoparticle ferumoxytol will supplement nonspecific gadolinium (Gd) MRI of brain tumors by targeting phagocytic cells rather than tumor cells; B) Dynamic contrast imaging of perfusion, permeability and angiography with ferumoxytol will improve visualization of vascular injury at the blood-brain barrier (BBS) compared to Gd, due to minimal vascular leak at early time points; C) Labeling white blood cells with a different iron oxide nanoparticle, ferumoxides, in combination with protamine will allow tracking of this "cellular contrast agent" into CNS tumors, initially in animal models, and if feasible in humans later in the funding period. Specific Aim 1 will compare dynamic and conventional MR imaging with histological imaging of vascular changes and inflammation at the BBB, using state-of-the-art high Tesla MR scanners. Vascular changes due to cancer therapies or steroids will be evaluated in animal models of glioblastoma and CNS metastasis. In Specific Aim 2, in vivo labeling of peripheral inflammatory cells with ferumoxides/protamine will be optimized in animal studies. We will characterize the use of this cellular contrast agent in imaging the BBB and intracerebral tumors with both MR and histological correlation. Specific Aim 3 will assess vascular and inflammatory changes at the BBB in neoplastic CNS lesions in a clinical trial comparing ferumoxytol magnetic nanoparticles and Gd at both 3T and 7T. Dynamic imaging, MR angiography and MRI will be performed in four subject groups: glioblastoma or metastatic CNS malignacy stratified by prior chemotherapy and/or radiation therapy. In Specific Aim 4, we propose to develop a Phase I clinical trial of the safety of ferumoxides/protamine and the potential to label circulating dendritic cells, to assess transvascular migration in tumor at both 3T and 7T. We hypothesize that state-of- the-art high Tesla MR imaging of nanoparticle perfusion and delivery in both animal brain tumor models and clinical trials may identify tumor responses before tumor shrinkage can be detected on conventional imaging. This proposal is responsive to PAS-03-165.

在本提案中，我们将测试总体假设，即高特斯拉磁共振 (MR) 成像磁性氧化铁纳米颗粒将增加定量灌注数据和细胞特异性成像神经血管单元到中枢神经系统 (CMS) 转移和胶质母细胞瘤的经典解剖 MR。我们建议测试三个主要假设：A) 纳米颗粒 ferumoxytol 将补充非特异性通过靶向吞噬细胞而不是肿瘤细胞对脑肿瘤进行钆 (Gd) MRI； B) 动态使用费鲁莫托进行灌注、渗透性和血管造影的对比成像将改善血管造影的可视化与 Gd 相比，血脑屏障 (BBS) 处的血管损伤较小，因为早期血管渗漏极少点； C) 用不同的氧化铁纳米颗粒（亚铁氧化物）结合鱼精蛋白将允许追踪这种“细胞造影剂”进入中枢神经系统肿瘤，最初是在动物模型中，如果在资助期后期在人类中可行。具体目标 1 将比较动态 MR 和传统 MR 使用最先进的技术对 BBB 处的血管变化和炎症进行组织学成像高特斯拉 MR 扫描仪。癌症治疗或类固醇引起的血管变化将在动物身上进行评估胶质母细胞瘤和中枢神经系统转移模型。在具体目标 2 中，外周炎症的体内标记含有氧化铁/鱼精蛋白的细胞将在动物研究中得到优化。我们将描述这个的使用细胞造影剂在 MR 和组织学成像中对 BBB 和脑内肿瘤进行成像相关性。具体目标 3 将评估肿瘤性中枢神经系统 BBB 的血管和炎症变化一项临床试验中比较 Ferumoxytol 磁性纳米颗粒和 Gd 在 3T 和 7T 下的损伤。动态的成像、MR 血管造影和 MRI 将在四个主题组中进行：胶质母细胞瘤或转移性中枢神经系统通过先前的化疗和/或放射治疗对恶性肿瘤进行分层。在具体目标 4 中，我们建议开展一项关于氧化铁/鱼精蛋白安全性和标记循环的潜力的 I 期临床试验树突状细胞，以评估 3T 和 7T 肿瘤中的跨血管迁移。我们假设状态- 动物脑肿瘤模型和动物脑肿瘤模型中纳米颗粒灌注和输送的最先进的高特斯拉 MR 成像临床试验可以在常规成像检测到肿瘤缩小之前确定肿瘤反应。该提案响应 PAS-03-165。