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

摘要

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.