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，我们将测试以下总体假设：使用磁性氧化铁纳米颗粒的高特斯拉磁共振（MR）成像将为中枢神经系统（CMS）转移瘤和胶质母细胞瘤的经典解剖MR增加定量灌注数据和神经血管单位的细胞特异性成像。我们提出测试三个主要假设：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，由于早期时间点的最小血管渗漏，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）处血管损伤的可视化; C）用不同的氧化铁纳米颗粒ferumoxides与鱼精蛋白组合标记白色血细胞将允许跟踪这种“细胞造影剂”进入CNS肿瘤，最初在动物模型中，如果可行的话，在资助期后期在人类中。具体目标1将使用最先进的高特斯拉MR扫描仪，比较动态和常规MR成像与BBB血管变化和炎症的组织学成像。将在胶质母细胞瘤和CNS转移的动物模型中评价癌症治疗或类固醇引起的血管变化。在特定目标2中，将在动物研究中优化Ferumoxides/鱼精蛋白对外周炎性细胞的体内标记。我们将通过MR和组织学相关性来描述这种细胞造影剂在BBB和脑内肿瘤成像中的使用。具体目标3将在比较3 T和7 T下的ferumoxytol磁性纳米颗粒和Gd的临床试验中评估肿瘤性CNS病变中BBB处的血管和炎症变化。将在4个受试者组中进行动态成像、MR血管造影和MRI：按既往化疗和/或放疗分层的胶质母细胞瘤或转移性CNS肿瘤。在具体目标4中，我们建议开展一项关于ferumoxides/鱼精蛋白安全性和标记循环树突状细胞潜力的I期临床试验，以评估3 T和7 T下肿瘤的经血管迁移。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MR成像可以在常规成像检测到肿瘤收缩之前识别肿瘤反应。本提案是对PAS-03-165的回应。

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.