Time Domian Electron Paramagnetic Resonance Imaging

A)确定EPRI的固有空间、光谱(生理)和时间分辨率，并与来自MRI的图像进行联合配准。利用部分k空间提高了时间分辨率。图像数据采集策略研究了控制空间、光谱和时间分辨率的基本因素，以了解在活体实验中实际可实现的分辨率。这是一个重要的因素，当分析时，将允许进行体内实验，以提出与生理动力学和肿瘤中的生理波动有关的基本问题，这是到目前为止还不可能的。我们仔细研究了决定EPRI固有分辨率的因素，并开发了图像形成策略来优化EPRI数据集，以获得最佳的空间、时间和光谱(生理)分辨率。随着对空间、光谱和时间分辨率因素的了解，我们已经能够优化和提高它们。此外，我们借鉴了MRI的概念，如压缩传感和部分k空间成像策略，能够在不牺牲空间和光谱维度的情况下，在短短1分钟内收集图像，获得完整的3维图像数据。有了这一能力，我们已经能够探测肿瘤PO2的微妙时间波动，也能够区分慢性和循环缺氧。我们还在小鼠胶质母细胞瘤模型中实现了pO2的成像，这是我们首次能够证明pO2图的可行性。b)对较大尺寸物体进行成像的策略：我们通过整合EPR射频链和控制梯度放大器，重新设计了一款低场MRI扫描仪，以用作EPRI pO2成像器。这种磁铁有80厘米的直径，可以用来研究更大的物体。我们已经开发了成像机架，其中可以收集pO2图像，并将对象移动到相邻的以1.0T操作的MRI扫描仪，以收集可以与pO2地图共同配准的解剖图像。这使得增加可以进行的研究的数量成为可能。C)使用影响微循环的药物治疗时肿瘤生理的时间分布。利用EPR在接受雷帕霉素治疗时监测肿瘤pO2和血容量变化的能力，我们发现在开始治疗后的一段时间内，肿瘤pO2出现一过性增加，并伴随着血管密度的下降，这符合血管重新正常化的假设，此外还抑制了mTOR途径。d)确定诱导暂时缺氧的策略以增强缺氧细胞毒素的有效性：我们一直在使用超极化丙酮酸作为示踪剂进行代谢磁共振成像。我们研究了丙酮酸推注对肿瘤PO2谱的影响，并证明丙酮酸在推注剂量后立即引起缺氧，持续4小时。这是在使用低氧敏感药物方面的一个重要发现。我们发现，在缺氧性肿瘤中，TH-302等缺氧性细胞毒素的疗效可以通过预先用丙酮酸治疗而增强，丙酮酸会导致短暂的缺氧性。TH-302的增强疗效被解释为将肿瘤缺氧带入放射生物缺氧。

a) Determining and intrinsic spatial, spectral (physiologic) and temporal resolution of EPRI and co-registration with images from MRI. Improving the temporal resolution using ?partial k-space? image data acquisition strategiesThe fundamental spectrometer dependent factors governing the spatial, spectral and temporal resolutions have been studied to understand the practically realizable resolutions in vivo experiments. This is an important factor which when analyzed will permit conducting in vivo experiments to ask fundamental questions pertaining to the dynamics of physiology and physiological fluctuations in tumors, which has not been possible till now. We have critically examined factors involved in determining the intrinsic resolution in EPRI and developed image formation strategies to optimize the EPRI data sets for optimal spatial, temporal and spectral (physiologic) resolutions. With an understanding of the factors governing the spatial, spectral and temporal resolutions, we have been able to optimize and improve the same. Additionally, we have borrowed concepts from MRI such as compressed sensing and partial k-space imaging strategies and have been able to collect images in as little as 1 minute for a full 3-dimensional image data without sacrificing the spatial and spectral dimensions. With this capability, we have been able to probe the subtle temporal fluctuations in tumor pO2 and also distinguish chronic and cycling hypoxia. We have also implemented imaging of pO2 in glioblastoma models in mice where for the first time we have been able to demonstrate the feasibility of pO2 maps.b) Strategies for imaging larger sized objects:We have redesigned a low field MRI scanner to operate as an EPRI pO2 imager by integrating the EPR RF chain and controlling the gradient amplifiers. The magnet has an 80 cm bore and permits the study of larger objects. We have developed imaging gantries where it is possible to collect pO2 images and move the object to an adjacent MRI scanner operating at 1.0 T to collect anatomical images which can be co-registered with pO2 maps. This has made it possible to increase the number of studies which can be performed. c) Temporal profile of tumor physiology when treated with drugs which impact microcirculation. Using the capability of EPR to monitor changes in tumor pO2 and blood volume when treated with rapamycin, we found that there is a period after initiating treatment where there is a transient increase in tumor pO2 with an accompanying decrease in blood vessel density consistent with the hypothesis of vascular re-normalization in addition to inhibiting mTOR pathways.d) Identification of strategies to induce temporary hypoxia to enhance the efficacy of hypoxic cytotoxins:We have been conducting metabolic MRI using hyperpolarized pyruvic acid as the tracer. We examined the effect of bolus pyruvate injection on tumor pO2 profiles and demonstrated that pyruvate induces hypoxia immediately after a bolus dose which is sustained for 4 hours. This is an important finding in using hypoxia sensitive drugs. We found that in hypoxic tumors, the efficacy of hypoxic cytotoxins such as TH-302 is enhanced by prior treatment with pyruvate which induces hypoxia transiently. The enhanced efficacy of TH-302 is explained as bring the tumor hypoxia into radiobiologic hypoxia.