Time Domian Electron Paramagnetic Resonance Imaging

时域电子顺磁共振成像

• 批准号: 8175326
• 负责人: murali cherukuri
• 金额: $ 84.24万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8175326
• 关键词: Accounting; Acute; Aftercare; Agreement; Air; Anatomy; Angiogenesis Inhibitors; Animals; Ants; Autophagocytosis; Blood Vessels; Blood flow; Bolus Infusion; Carbogen; Chemicals; Chronic; Collection; Data; Data Set; Development; Diffusion; Electrodes; Electron Spin Resonance Spectroscopy; Exhibits; Goals; Human; Hypoxia; Image; Imaging Techniques; Implant; Inbred C3H Mice; Injection of therapeutic agent; Investigation; Leg; Magnetic Resonance Imaging; Maps; Metabolic; Microscopic; Modality; Modeling; Monitor; Mus; Neoplasms in Vascular Tissue; Oxygen; Pattern; Pericytes; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Physiology; Procedures; Process; Radiation; Radiation therapy; Research Design; Resistance; Resolution; Respiration; Scanning; Sirolimus; Squamous cell carcinoma; System; Time; Tissues; Tracer; Transplantation; Treatment Efficacy; Tumor Oxygenation; base; chemotherapy; density; imaging modality; improved; in vivo; instrumentation; mTOR Inhibitor; malignant phenotype; prototype; research study; response; scale up; tumor

Project Summary: The current Electron Paramagnetic Resonance imaging system developed as a prototype in vivo oxygen imaging scanner with anatomic correlates obtained from conventional Magnetic Resonance Imaging (MRI) and additional information such as blood vessel density makes use of a combined resonator for both the modalities allowing reliable coregistration of spatial information from both imaging scans. Subsequent developments focused on improving the spatial and temporal resolutions. The EPR imaging system with the developments during the last year now has the following capabilities: A) An image data set can be obtained in 2 minutes permitting the collection of about 8-10 images after a single bolus injection of the tracer Oxo63, allowing the assessment of temporal changes in tumor oxygen status. B) monitoring changes in tumor oxygen status longitudinally over a period of several days-weeks to assess drug induced changes in oxygen status and correlate with treatment efficacy. With these improvements, w have utilized the system for longitudinal monitoring of tumor oxygen status, blood vessel density and the corresponding changes in response to treatment with chemotherapeutic drugs which impact tumor oxygen status and blood vessel density. Based on these capabilities, the following three experiments are being pursued: 1) Assessment of cycling (acute) hypoxia in tumors: Tumors, as a result of their aberrant vasculature have both chronic (diffusion limited) and cycling (acute) hypoxia. While chronic hypoxia is diffusion limited, acute hypoxia has been shown to coner phenotypes which display resistance to treatment and also a more malignant phenotype. While this phenomenon has either been studied using invasive approaches such as insertion of oxygen sensing electrodes or such a pattern enforced experimentally, imaging techniques so far have not been able to study and distinguish the two types of hypoxia. In a study designed to examine this phenomenon using EPR, two tumor models (SCC VII and HT 29) implanted in mice were studied to assess the levels of both chronic and cycling hypoxia. MRI studies were sequentially carried out to obtain anatomic correlates as well as blood vessel density. Histological correlates from tumor sections were also evaluated for blood vessel density and vascular integrity. Air-Carbogen-Air challenge via respiration was also imposed to examine the spatio-temporal responses to tumor oxygen to distinguish chronic vs cycling hypoxic regions. The studies reveal that both tumor types studied exhibited cycling hypoxia, withtyhe SCC VII transplant exhibiting fluctuations to a large magnitude compared to HT 29 tumors. The relatively stronger pericyte coverage in HT 29 tumor vasculature was accounted for the observed differences. 2) Effect of the anti-angiogenic drug, sunitinib on tumor oxygenation and blood vessel density: Ant-angiogenic drugs have been shown to transiently increase tumor oxygen levels after treatment initiation through a process called vascular re-normalization. This is followed by a steady decrease in oxygen resulting from loss of blood vessels. The vascular renormalization period is a window in time for synergy with radiotherapy or chemotherapy. We have evaluated the effect of sunitinib, an anti-angiogenic drug in C3H mice implanted with squamous cell carcinoma (SCC) on the hind leg and monitored changes in oxygen and blood vessel density on several days after treatment initiation and compared with control untreated tumor bearing mice. These studies showed: a) it is possible to longitudinally monitor changes in tumor oxygen and blood vessel density; b) blood vessel density decreases after treatment with sunitinib; and d) there is a transient increase in tumor oxygenation after sunitinib treatment. These data are in agreement with the immunohistochemical data obtained on the markers for blood vessel density. An important finding is that EPR imaging studies can identify the vascular renormalization period in tumors during which time we find that there is a significant synergy when radiotherapy is administered. Another finding is that fluctuations in oxygen are minimized during the period of vascular re-normalization. 3) Effect of the mTOR inhibitor, rapamycin on tumor oxygenation and blood vessel density: Rapamycin is in active investigation in many tumor types in humans. Some of its effects on tumors include autophagy and tumor vessel damage. EPR imaging and MRI studies were conducted on SCC tumor bearing mice during treatment with rapamycin. The studies show that rapamycin has significant influence in tumor vessel damage as early as one day after treatment initiation. However, the tumor vessel decrease was associated with a transient but significant increase in tumor oxygenation in agreement with results which suggest that there is a normalization of tumor vasculature which increases tumor oxygenation.

项目摘要：当前的电子顺磁共振成像系统作为原型在体内氧成像扫描仪中开发，具有从传统的磁共振成像（MRI）获得的解剖相关性（MRI），以及其他信息（例如血管密度）的其他信息，可以使两种可靠的核心核能信息的组合共振剂使用spatial spatial Impatigation Imaging scanging scanging scing secing secting secantiation。随后的发展集中于改善空间和时间分辨率。 EPR成像系统与上一年的开发系统现在具有以下功能：a）可以在2分钟内获得图像数据集，从而在单次注射示踪剂Oxo63后收集约8-10张图像，从而评估肿瘤氧状态的时间变化。 b）在几天周期内纵向监测肿瘤氧状况的变化，以评估药物诱导的氧气状态变化并与治疗功效相关。通过这些改进，W利用该系统用于纵向监测肿瘤氧状况，血管密度和相应的变化，以应对化学治疗药物的治疗，从而影响肿瘤氧状况和血管密度。基于这些能力，正在进行以下三个实验：1）评估肿瘤中循环（急性）缺氧的评估：由于它们异常脉管系统，肿瘤既具有慢性（扩散限制）和循环（急性）缺氧。尽管慢性缺氧是扩散有限的，但急性缺氧表现出对治疗的抗药性以及更恶性表型的表现。尽管已使用侵入性方法（例如插入氧气传感电极的插入）进行了研究，或者是通过实验强制执行的这种模式，但到目前为止，成像技术尚未能够研究和区分两种类型的缺氧。在一项旨在使用EPR检查这种现象的研究中，研究了植入小鼠中的两个肿瘤模型（SCC VII和HT 29），以评估慢性和循环缺氧的水平。依次进行MRI研究以获得解剖相关性以及血管密度。还评估了血管密度和血管完整性的组织学相关性。还施加了通过呼吸来进行空气 - 加入空气挑战，以检查对肿瘤氧的时空反应，以区分慢性循环缺氧区域。研究表明，与HT 29肿瘤相比，两种研究的肿瘤类型均表现出循环缺氧，伴有SCC VII移植，其波动幅度很大。 HT 29肿瘤脉管系统中相对较强的周细胞覆盖范围被观察到了差异。 2）抗血管生成药物，舒尼替尼对肿瘤氧合和血管密度的影响：通过称为血管重新分布化的过程，已经证明抗抗血管生成药物可以在治疗起始后瞬时增加肿瘤氧水平。接下来是由于血管损失而导致的氧气稳定减少。血管重归其化期是与放射疗法或化学疗法协同作用的时间窗口。我们已经评估了Sunitinib，Sunitinib是一种抗血管生成药物对鳞状细胞癌（SCC）植入后腿的C3H小鼠的作用，并在治疗开始后几天监测了氧气和血管密度的变化，并与对照未经处理的肿瘤轴承小鼠进行了比较。这些研究表明：a）可以纵向监测肿瘤氧和血管密度的变化； b）用舒尼尼治疗后血管密度降低； d）舒尼替尼治疗后肿瘤氧合的瞬时增加。这些数据与在血管密度标记上获得的免疫组织化学数据一致。一个重要的发现是，EPR成像研究可以识别肿瘤中的血管重生时期，在此期间，我们发现在放疗时会有明显的协同作用。另一个发现是，在血管重新归一化期间，氧气的波动被最小化。 3）MTOR抑制剂，雷帕霉素对肿瘤氧合和血管密度的影响：雷帕霉素正在积极研究人类的许多肿瘤类型。它对肿瘤的某些影响包括自噬和肿瘤血管损伤。在用雷帕霉素治疗期间，对SCC肿瘤轴承小鼠进行了EPR成像和MRI研究。研究表明，雷帕霉素早在治疗开始后的一天就对肿瘤血管损伤具有显着影响。然而，肿瘤血管减少与瞬时但显着增加的肿瘤氧合与结果一致，这表明肿瘤脉管系统的归一化可以增加肿瘤的氧合。