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

描述(申请人提供)：在这项提案中，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)成像将在中枢神经系统(CMS)转移瘤和胶质母细胞瘤的经典解剖MR的基础上增加神经血管单位的定量灌注数据和细胞特异性成像。我们建议检验三个主要假设：a)纳米阿魏酸甘油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Gd(Gd)MRI；b)与阿魏酸甘油相比，阿魏酸甘油的灌注、通透性和血管造影术的动态对比成像将提高血脑屏障(BBS)血管损伤的可视化，因为早期时间点的血管泄漏很少；c)用不同的氧化铁纳米颗粒标记白细胞，亚铁氧化物与鱼精蛋白联合使用，将使这种“细胞造影剂”能够在最初的动物模型中追踪到CNS肿瘤，如果可行，在稍后的资助期将在人类中进行追踪。具体目标1将使用最先进的高特斯拉磁共振扫描仪，将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成像进行比较。肿瘤治疗或类固醇引起的血管变化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。在具体目标2中，将在动物实验中优化用亚铁氧化物/鱼精蛋白标记外周炎症细胞的体内标记。我们将描述这种细胞造影剂在血脑屏障和脑内肿瘤的MR成像和组织学相关成像中的应用。具体目标3将在一项临床试验中评估肿瘤CNS病变中血脑屏障的血管和炎症变化，该临床试验比较了阿魏酸甘油磁性纳米颗粒和Gd在3T和7T下的变化。将对四组受试者进行动态成像、磁共振血管成像和核磁共振成像：胶质母细胞瘤或根据既往化疗和/或放射治疗分层的转移性中枢神经系统恶性肿瘤。在具体目标4中，我们建议开展一项关于亚铁氧化物/鱼精蛋白的安全性和标记循环树突状细胞的可能性的I期临床试验，以评估3T和7T下肿瘤的跨血管迁移。我们假设，在动物脑瘤模型和临床试验中，最先进的高特斯拉磁共振纳米颗粒灌注和输送成像可以在常规成像检测到肿瘤缩小之前识别肿瘤反应。本提案是对PAS-03-165的响应。

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.