Enhancing in vivo EPR imaging using spin probes with short relaxation times

使用弛豫时间短的自旋探针增强体内 EPR 成像

基本信息

批准号：
8577463
负责人：
Mark Tseytlin
金额：
$ 14.42万
依托单位：
UNIVERSITY OF DENVER (COLORADO SEMINARY)
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577463
关键词：
Animals Award Biology Blood - brain barrier anatomy Brain Cell membrane Cell physiology Cells Characteristics Charge Chemistry Chicago Clinical Complement Detection Development Development Plans Drug Design Electron Spin Resonance Spectroscopy Electrons Frequencies Goals Grant Image Imaging Techniques Intracellular Space Learning Leg MRI Scans Magnetic Resonance Imaging Maps Mathematics Measurement Measures Medicine Mentors Metabolic Methodology Methods Monitor Mus Nitrogen Noise Outcome Oxygen Oxygen saturation measurement Peripheral Vascular Diseases Pharmacotherapy Physics Physiologic pulse Physiological Physiology Positioning Attribute Positron-Emission Tomography Radiation Radiation therapy Relative (related person)Relaxation Reporting Research Design Scanning Signal Transduction Spectrum Analysis Structure Testing Therapeutic Intervention Time Tissues Training Universities Work Wound Healing Writing base design extracellular imaging modality improved in vivo magnetic field method development neoplastic cell nitroxyl pre-clinical public health relevance research study skills therapy design tumor

项目摘要

DESCRIPTION (provided by applicant): Imaging of localized oxygen concentration (oximetry) and pH are key to the timing and sculpting of radiation treatment of tumors, improvement of wound healing, and design of therapy for peripheral vascular disease and for drug design. Electron paramagnetic resonance (EPR) imaging using trityl or nitroxide radical probes is under development for pre-clinical and clinical oximetry. Pulsed methods have been used to improve signal-to-noise and reduce the time to acquire an image with trityl radicals. Nitroxide radicals have advantages over trityl radicals because they can be prepared with structures that facilitate crossing the blood-brain barrier or targeting of intracellular spaces. Nitroxides also can be designed to monitor local pH, which has dramatic impact on therapeutic interventions for tumors. With current EPR methodology it is difficult to apply pulse methods to nitroxides because these radicals have shorter electron spin relaxation times than trityls. In Aim 1 a new method is proposed to improve the signal-to-noise in pulsed imaging of nitroxides which will enhance measurement of pO2. It is based on a bimodal resonator design where excitation and detection resonators are decoupled by tuning to different frequencies. Rapid sinusoidal scans will be used to permit excitation of the spins at the frequency of resonator 1 and detection of a two-pulse echo at the frequency of resonator 2. The method will be tested on phantoms at the University of Denver. In Aim 2 the proposed method will be implemented for in vivo oximetry in mouse tumors at the University of Chicago EPR Center, working collaboratively with co- mentor Prof. Halpern. The proposed new method will be quantitatively compared with the currently used methods. The time spent by the PI in Chicago will also be used to acquire practical skills in animal handling and designing in vivo experiments. In Aim 3 the PI will design and implement rapid scan EPR imaging experiments to measure pH using nitroxide radicals for which spectra are pH-dependent which can be targeted for either extracellular or intracellular domains. Complementary MRI scans will be used for co-registration of anatomical features, as well as for PI training purposes. This work will not be dependent on the outcome of Aims 1 and 2, so it can be done in parallel. Throughout the grant period the PI will take courses in biology, chemistry, and fundamentals of medicine to complement his strong background in mathematics and physics and bring him to a level where he can design and interpret tumor physiology imaging experiments, and evaluate drug and radiation therapies as an independent PI. The work on Aims 1, 2, and 3 will be performed increasingly independently during the three year award period. The work will provide the preliminary results needed to write an R01 proposal related to imaging in brain.

描述（由申请人提供）：局部氧浓度（血氧仪）和pH的成像是肿瘤放射治疗的时间和雕刻的关键，改善伤口愈合以及对周围血管疾病的治疗设计以及药物设计的关键。使用Trityl或氮氧化物自由基探针进行电子顺磁共振（EPR）成像正在开发用于临床前和临床血氧饱和度。脉冲方法已用于改善信号到噪声，并减少用三利自由基获取图像的时间。氮氧化物比三能型自由基具有优势，因为它们可以用促进跨越血脑屏障或靶向细胞内空间的结构制备。氮氧化物还可以设计用于监测局部pH，这对肿瘤的治疗干预措施产生了巨大影响。使用当前的EPR方法，很难将脉冲方法应用于硝基氧化物，因为这些自由基的电子自旋松弛时间比Trityls短。在AIM 1中，提出了一种新方法来改善氮氧化物的脉冲成像中的信噪，这将增强PO2的测量。它基于双峰谐振器设计，通过调谐到不同的频率，激发和检测谐振器被解耦。快速正弦扫描将用于允许以谐振器1的频率激发自旋，并以谐振器2的频率检测两脉冲回声。该方法将在丹佛大学的幻影上进行测试。在AIM 2中，将在芝加哥大学EPR中心的小鼠肿瘤中实施拟议的方法，以与合作社Halpern教授合作。提出的新方法将与当前使用的方法进行定量比较。 PI在芝加哥花费的时间也将用于获得动物处理和设计体内实验的实用技能。在AIM 3中，PI将设计和实施快速扫描EPR成像实验，以使用氮氧化物自由基对pH值进行pH值依赖性pH依赖性，这可以针对细胞外或细胞内域。互补的MRI扫描将用于共同注册解剖特征以及PI培训目的。这项工作将不取决于目标1和2的结果，因此可以并行完成。在整个赠款期间，PI将学习生物学，化学和医学基础知识的课程，以补充他在数学和物理学方面的强大背景，并将他提升到他可以设计和解释肿瘤生理成像实验的水平，并评估药物和辐射疗法作为独立的PI。在三年奖励期间，AIMS 1、2和3的工作将越来越独立。这项工作将提供与大脑成像有关的R01提案所需的初步结果。