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

摘要 许多低氧过程与淀粉样斑块的发展在病理上相关。 阿尔茨海默病(AD)。然而，淀粉样蛋白b斑块(Ab)的局部发展尚未得到 成功地与局部脑缺氧相关。我们认为，低氧基因座登记的重要性在 脑内有抗体发生的部位将使临床对抗体反应的准确评估成为可能 干预以缓解AD过程中的低氧基因座。我们资助的研究基金R01 CA236385，如上面摘要中所述，将使用18F-咪唑改善PET乏氧成像 (FMISO)结合两种临床可用的MRI定位抗辐射缺氧肿瘤区域 方法：动态增强磁共振成像(DCE-MRI)和碘帕米多化学交换饱和转移 磁共振成像(ICEST-MRI)。检测低氧血氧饱和度肿瘤区域的金标准是电子 顺磁共振PO2成像(EPRpO2成像)。本补充剂供应公告不是- AD-20-034作为一般补充基金机会公告的一部分，PA-18-591提供了 独特的机会将成像局部缺氧的应用从抗癌扩展到第二次， 相当独特且普遍至关重要的健康问题：阿尔茨海默氏症(AD)。开发一种新的 临床前影像方法学用于筛选可调节局部脑缺氧的干预措施 将为缓解AD提供信息的突破性信息。我们建议使用一种新技术来注入 通过实质内途径包裹定量EPRpO2的介孔二氧化硅纳米管(MSN) 我们最近发布的传感器，用来为当地的PO2成像。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和C57BL/6的大脑中的β 控制和APP/PS1 AD鼠标模型。我们将AD的这个生物标记物的位置与 小鼠大脑中的低PO2。低氧标志物FMISO和DCE分布的附加PET图像 将获得用于测量血流灌注的MRI和用于评估组织pH的ICEST-MRI。将使用核磁共振成像 为了校正FMISO PET图像以更好地符合EPRpO2图像，导致了一种新的算法 应用FMISO PET和DCE-MRI及CEST-MRI方法对受试者进行临床成像 定位AD和相关痴呆患者的大脑中的缺氧，并确定这种缺氧的缓解是否可以 缓解AD流程。

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.