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

在这项提案中，我们将测试高特斯拉磁共振(MR)成像的总体假设 磁性氧化铁纳米颗粒将增加定量血流灌注数据和细胞特异性成像 神经血管单位到中枢神经系统(CMS)转移瘤和胶质母细胞瘤的经典解剖MR。 我们建议检验三个主要假设：a)纳米阿魏酸甘油酯将补充非特异性 靶向吞噬细胞而不是肿瘤细胞的脑肿瘤的Gd磁共振成像；B)动态 阿魏酸甘油酯的灌注、通透性和血管造影术的对比成像将提高 血脑屏障(BBS)的血管损伤与Gd相比，由于早期血管渗漏较少 点；c)用不同的氧化铁纳米颗粒--铁氧化物--标记白血球 鱼精蛋白将允许这种“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 在资助期晚些时候，在人类身上是可行的。具体目标1将比较动态磁共振和常规磁共振 使用最先进的技术，对血脑屏障的血管变化和炎症进行组织成像 高特斯拉磁共振扫描仪。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。在特定目的2，外周炎症的体内标记 含有亚铁氧化物/鱼精蛋白的细胞将在动物实验中得到优化。我们将描述一下它的用法 细胞对比剂在血脑屏障和脑内肿瘤MR和组织学成像中的应用 相关性。特异性目标3将评估肿瘤中枢神经系统血脑屏障的血管和炎症变化 在一项临床试验中，比较了阿魏酸甘油磁性纳米颗粒和Gd在3T和7T下的损害。动态 将对四组受试者进行成像、磁共振血管成像和核磁共振成像：胶质母细胞瘤或转移性中枢神经系统 因既往化疗和/或放射治疗而分层的恶性肿瘤。在具体目标4中，我们建议 开展阿魏酸钠/鱼精蛋白的安全性和标记循环的可能性的I期临床试验 树突状细胞，以评估肿瘤在3T和7T时的跨血管迁移。我们假设状态是- 纳米粒子在动物脑瘤模型和脑肿瘤模型中的高特斯拉磁共振成像 临床试验可能会在常规成像检测到肿瘤缩小之前识别出肿瘤反应。 本提案是对PAS-03-165的响应。

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.