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

描述（由申请人提供）：在本提案中，我们将测试总体假设，即磁性氧化铁纳米颗粒的高特斯拉磁共振（MR）成像将在中枢神经系统（CMS）转移和胶质母细胞瘤的经典解剖MR中增加神经血管单元的定量灌注数据和细胞特异性成像。我们提出验证三个主要假设：A)纳米颗粒阿魏木糖醇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，阿魏木醇灌注、通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，因为在早期时间点血管泄漏最小；C)用一种不同的氧化铁纳米颗粒（阿鲁氧化铁）与鱼精蛋白结合标记白细胞，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，如果可行的话，将在资助期后期用于人体。Specific Aim 1将使用最先进的高特斯拉磁共振扫描仪，比较动态和常规磁共振成像与血脑屏障血管变化和炎症的组织学成像。肿瘤治疗或类固醇引起的血管改变将在胶质母细胞瘤和中枢神经系统转移的动物模型中进行评估。在Specific Aim 2中，将在动物研究中优化用阿魏氧化物/鱼精蛋白在体内标记外周炎症细胞。我们将描述这种细胞造影剂在血脑屏障和脑内肿瘤成像中的应用，包括MR和组织学相关性。特异性目的3将在比较阿魏木糖醇磁性纳米颗粒和Gd在3T和7T时的临床试验中评估肿瘤性中枢神经系统病变血脑屏障的血管和炎症变化。动态成像、MR血管造影和MRI将在四组受试者中进行：胶质母细胞瘤或转移性中枢神经系统恶性肿瘤，经既往化疗和/或放疗分层。在Specific Aim 4中，我们建议开展一项I期临床试验，以验证阿鲁莫氧化物/鱼精蛋白的安全性，以及标记循环树突状细胞的潜力，以评估肿瘤在3T和7T时的跨血管迁移。我们假设，在动物脑肿瘤模型和临床试验中，最先进的纳米颗粒灌注和递送的高特斯拉磁共振成像可以在常规成像检测到肿瘤缩小之前识别肿瘤反应。此提案响应PAS-03-165。

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.