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

在本提案中，我们将测试高特斯拉磁共振（MR）成像与 磁性氧化铁纳米颗粒将增加定量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。 我们建议测试三个主要假设：A）纳米颗粒ferumoxytol将补充非特异性 通过靶向吞噬细胞而不是肿瘤细胞的脑肿瘤的钆（Gd）MRI; B）动态 用ferumoxytol进行灌注、渗透性和血管造影的对比成像将改善 与Gd相比，血脑屏障（BBS）处的血管损伤，由于早期的血管渗漏极小 C）用不同的氧化铁纳米颗粒ferumoxides标记白色血细胞 鱼精蛋白将允许跟踪这种“细胞造影剂”进入CNS肿瘤，最初在动物模型中，如果 在资助期后期对人类可行。特定目标1将比较动态和传统MR 使用最先进的技术，对BBB处的血管变化和炎症进行组织学成像 高特斯拉磁共振扫描仪将在动物中评价癌症治疗或类固醇引起的血管变化 胶质母细胞瘤和CNS转移的模型。在特定目标2中，外周炎性细胞的体内标记 含有铁氧化物/鱼精蛋白的细胞将在动物研究中进行优化。我们将描述使用这种 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 相关性特定目标3将评估肿瘤性CNS中BBB的血管和炎症变化 在3 T和7 T下比较ferumoxytol磁性纳米颗粒和Gd的临床试验中的病变。动态 将在四个受试者组中进行成像、MR血管造影和MRI：胶质母细胞瘤或转移性CNS 按既往化疗和/或放疗分层的生存率。在具体目标4中，我们建议 开展一项关于ferumoxides/鱼精蛋白安全性的I期临床试验， 树突状细胞，以评估在3 T和7 T下肿瘤中的经血管迁移。我们假设- 在动物脑肿瘤模型中纳米颗粒灌注和递送的最先进的高特斯拉MR成像， 临床试验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的回应。

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.