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：
7211181
负责人：
EDWARD A. NEUWELT
金额：
$ 56.45万
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/7211181
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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：在本提案中，我们将测试总体假设，即使用磁性氧化铁纳米颗粒的高特斯拉磁共振 (MR) 成像将在中枢神经的经典解剖 MR 中添加神经血管单元的定量灌注数据和细胞特异性成像系统（CMS）转移和胶质母细胞瘤。我们建议测试三个主要假设：A) 纳米颗粒 ferumoxytol 将通过靶向吞噬细胞而不是肿瘤细胞来补充脑肿瘤的非特异性钆 (Gd) MRI； B) 与 Gd 相比，使用 Ferumoxytol 进行灌注、渗透性和血管造影的动态对比成像将改善血脑屏障 (BBS) 血管损伤的可视化，因为早期时间点的血管渗漏最小； C）用不同的氧化铁纳米颗粒（铁氧化物）与鱼精蛋白结合标记白细胞，将能够追踪这种“细胞造影剂”进入中枢神经系统肿瘤，最初是在动物模型中，如果可行的话，在资助期后期也可以在人类中进行追踪。具体目标 1 将使用最先进的高特斯拉 MR 扫描仪，将动态和传统 MR 成像与血脑屏障血管变化和炎症的组织学成像进行比较。将在胶质母细胞瘤和中枢神经系统转移的动物模型中评估癌症治疗或类固醇引起的血管变化。在具体目标 2 中，将在动物研究中优化用氧化铁/鱼精蛋白体内标记外周炎症细胞。我们将描述这种细胞造影剂在 BBB 和脑内肿瘤成像中的用途，并具有 MR 和组织学相关性。具体目标 3 将在一项比较 3T 和 7T 下菲鲁莫托磁性纳米粒子和 Gd 的临床试验中评估肿瘤性 CNS 病变中 BBB 的血管和炎症变化。动态成像、MR 血管造影和 MRI 将在四个主题组中进行：胶质母细胞瘤或通过既往化疗和/或放疗分层的转移性 CNS 恶性肿瘤。在具体目标 4 中，我们建议开展一项 I 期临床试验，研究铁氧化物/鱼精蛋白的安全性以及标记循环树突状细胞的潜力，以评估 3T 和 7T 下肿瘤的跨血管迁移。我们假设，动物脑肿瘤模型和临床试验中纳米颗粒灌注和输送的最先进的高特斯拉磁共振成像可以在传统成像检测到肿瘤缩小之前识别肿瘤反应。该提案响应 PAS-03-165。