Improved Radiation Therapy of Hypoxic Tumor Regions by Integrated PET, EPR, and MR Imaging - Resubmission 01 - Revision - 1

摘要 许多缺氧过程与淀粉样斑块的形成在病理学上相关。 阿尔茨海默病（AD）。尽管如此，淀粉样蛋白-b 斑块 (Ab) 的局部发展尚未得到证实。 成功地与局部脑缺氧相关。我们认为缺氧位点登记的重要性 具有抗体发育位置的大脑将能够精确评估临床反应 干预以减轻缺氧位点，从而缓解 AD 过程。我们资助的研究补助金 R01 CA236385，如上面摘要中所述，旨在使用 18F-米索硝唑改善 PET 缺氧成像 (FMISO) 结合两种临床可用的 MRI 定位抗辐射缺氧肿瘤区域 方式：动态对比增强 MRI (DCE-MRI) 和碘帕醇化学交换饱和度转移 MRI（ICEST-MRI）。检测低 pO2（即缺氧）肿瘤区域的金标准是电子 顺磁共振 pO2 成像（EPRpO2 成像）。此补充可用性公告不- AD-20-034 作为一般补充基金机会公告 PA-18-591 的一部分提供了 将局部缺氧成像的应用从抗癌性扩展到第二个的独特机会， 非常独特且普遍重要的健康问题：阿尔茨海默病（AD）。的发展 筛选调节局部脑缺氧干预措施的临床前成像方法可能提供 突破性信息将为缓解 AD 提供信息。我们建议使用一种新技术来注入 通过实质内途径介孔二氧化硅纳米管 (MSN) 封装定量 EPRpO2 我们最近发布了用于本地 pO2 图像的传感器。这将克服血脑屏障的排斥 三酸 EPRpO2 传感器。这项工作将使用 18F 标记的 NAV4694 来定位 C57BL/6 大脑中的 Aβ 控制和 APP/PS1 AD 鼠标型号。我们将把 AD 生物标志物的位置与 小鼠大脑中的氧分压低。缺氧标记 FMISO 和 DCE 分布的附加 PET 图像 将获得用于测量灌注的 MRI 和用于评估组织 pH 值的 ICEST-MRI。核磁共振成像将被使用 校正 FMISO PET 图像，使其与 EPRpO2 图像更好地一致，从而产生了一种新颖的算法 在人类受试者中使用 FMISO PET 和 DCE-MRI 和 CEST-MRI 方法的临床成像方法 定位 AD 和相关痴呆症患者大脑中的缺氧情况，并确定缓解缺氧是否可以 减轻 AD 过程。

Abstract A number of hypoxic processes have been pathologically correlated with the development of amyloid plaque in Alzheimers's disease (AD). Nonetheless the local development of amyloid-b plaque (Ab) has not been successfully correlated with local brain hypoxia. We argue that the importance of registration of hypoxic loci in the brain with location of the development of Ab will enable the precise evaluation of the response of clinical intervention to mitigate hypoxic loci in the mitigation of the AD process. Our funded research grant R01 CA236385, as outlined in its abstract above, is to improve PET hypoxia imaging using 18F-Misonidazole (FMISO) in localizing radiation resistant hypoxic tumor regions incorporating two clinically available MRI modalities: dynamic contrast enhanced MRI (DCE-MRI) and Iopamidol chemical exchange saturation transfer MRI (ICEST-MRI). The gold standard for the detection of tumor regions with low pO2, i.e., hypoxic, is electron paramagnetic resonance pO2 imaging (EPRpO2 imaging). This supplement availability announcement NOT- AD-20-034 as part of the general supplement fundung opportunity announcement PA-18-591 provides a unique opportunity for expanding the application of imaging local hypoxia from cancer resistance to a second, quite distinct and generally crucial health problem: Alzeheimer's Disease (AD). The development of a preclinical imaging methodology to screen interventions that modulate local cerebral hypoxia may provide breakthrough information that will inform the mitigation of AD. We propose to use a novel technology to inject via an intraparenchymal route mesoporous silica nanotubes (MSNs) encapsulating the quantitative EPRpO2 sensor which we recently published to image local pO2. This will overcome the blood brain barrier exclusion of the triacid EPRpO2 sensor. The work will use 18F labeled NAV4694 to locate Aβ in the brain of both C57BL/6 control and APP/PS1 AD mouse models. We will correlate the location of this biomarker of AD with locations of low pO2 in the mouse brain. Additional PET images of the distribution of the hypoxia marker FMISO and DCE- MRI for measuring perfusion and ICEST-MRI for assessing tissue pH will be obtained. The MRIs will be used to correct the FMISO PET images to better agree with the EPRpO2 image, leading to a novel algorithm for using clinical imaging approaches of FMISO PET and DCE-MRI and CEST-MRI methods in human subjects to locate hypoxia in the brains of AD and related dementia patients and determine if mitigation of this hypoxia can mitigate the AD process.