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

摘要 许多缺氧过程在病理学上与脑梗死患者淀粉样斑块的形成相关。 阿尔茨海默病（AD）。尽管如此，淀粉样蛋白-b斑块（Ab）的局部发展还没有被证实。 成功地与局部脑缺氧相关联。我们认为，缺氧位点登记的重要性， 具有Ab发展位置的脑将使得能够精确评价临床治疗的反应。 干预以减轻缺氧位点在AD过程的缓解。我们的研究资助R 01 如上文摘要所述，CA 236385旨在使用18 F-米索咪唑改善PET缺氧成像 （FMISO）定位放射抵抗性缺氧肿瘤区域，结合两种临床可用的MRI 方法：动态增强MRI（DCE-MRI）和碘帕醇化学交换饱和转移 MRI（ICEST-MRI）。检测低pO 2肿瘤区域的金标准，即，缺氧，是电子 顺磁共振pO 2成像（EPRpO 2成像）。此补充供应公告不- AD-20-034作为一般补充资金机会公告PA-18-591的一部分， 独特的机会，扩大应用成像局部缺氧从癌症抗性到第二， 一种非常独特且普遍至关重要的健康问题：阿尔茨海默病（AD）。的发展 临床前成像方法，以筛选干预措施，调节局部脑缺氧可能提供 突破性的信息，这将有助于缓解AD。我们打算用一种新技术 通过实质内途径介孔二氧化硅纳米管（MSN）封装定量EPRpO 2 我们最近发布的用于成像局部pO 2的传感器。这将克服血脑屏障的排斥， 三元酸EPRpO 2传感器。本工作将使用18F标记的NAV 4694来定位Aβ在C57 BL/6和C57 BL/6小鼠脑中的位置。 对照和APP/PS1 AD小鼠模型。我们将把这种AD生物标志物的位置与 小鼠大脑中的低pO 2。缺氧标志物FMISO和DCE分布的额外PET图像- 将获得用于测量灌注的MRI和用于评估组织pH的ICEST-MRI。核磁共振成像将用于 校正FMISO PET图像，以更好地与EPRpO 2图像一致，从而产生一种新的算法， 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和相关痴呆患者大脑中的缺氧，并确定缓解这种缺氧是否可以 缓解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.