Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

奥豪瑟增强磁共振成像 (OMRI)

• 批准号: 8937744
• 负责人: murali cherukuri
• 金额: $ 109.12万
• 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/8937744
• 关键词: Aftercare; Anatomy; Biochemical; Biological Markers; Carbon; Cell Nucleus; Chemicals; Dependence; Dose; Glycolysis; Goals; Hypoxia; Image; Implant; In Vitro; Inbred C3H Mice; Label; Magnetic Resonance Imaging; Magnetism; Maps; Measures; Metabolic; Metabolism; Modeling; Monitor; Mus; Nature; Nude Mice; Oxides; Perfusion; Physiology; Production; Protons; Pyruvate; Radiation therapy; Reaction; Reactive Oxygen Species; Reporter; Signal Transduction; Site; Succinates; Techniques; Testing; Tracer; Water; aerobic glycolysis; base; density; extracellular; in vivo; interest; irradiation; molecular imaging; novel; pyrroline; research study; scale up; treatment effect; treatment response; tumor; tumor microenvironment

a) Serial imaging of tumor pO2 and metabolic profile in tumor bearing mice exposed to radiotherapy: The tumor microenvironment is characterized its unique physiology and metabolic profile which is characterized by hypoxia (low pO2) and acidotic (low pH) as a result of poor perfusion and aerobic glycolysis. These features provide imaging biomarkers such as tumor pO2 and glycolysis (pyruvate to lactate flux) which can be monitored to assess treatment response. Two tumor models were chosen for this study: SCCVII tumor implanted in C3H mice and HT29 tumor in nude mice. We first demonstrated using phantom objects, the capability to sequentially image pO2 and glycolysis and co-registering these two maps with anatomic images. After this, we chose two different tumor models based on their differing tumor microenvironment and imaged sequentially the pO2 maps and the conversion of the injeccted pyruvate being converted to lactate through glycolysis and co-registered with anatomic images. Tis enabled examining the dependence of tumor glycolysis on tumor pO2. Of the two tumors studied, SCCVII tumor was more glycolytic compared to HT29 tumors, consistent with the more hypoxic nature of the former. Further there was a spatial match between hypoxia and elevated glycolysis in SCCVII tumor. Upon irradiation (5 Gy) fractional hypoxia increased in these tumors. This was supported by measuring the extracellular acidification rates measured in tumors excised and studied in vitro my monitoring the lactate production. These studies suggest that the two imaging biomarkers can become useful in planning radiation therapy where the dose can be planned based on the spatial features of tumor pO2 status. b) Novel 13C labeled tracers for hyperpolarized MRI: The following features are necessary in a 13C labeled tracer to be implemented in in vivo applications: i) The molecule should be non-toxic at the levels administered for in vivo metabolic imaging; ii) it should have a carbon site which has a long T1; iii) It should participate in metabolic reactions or reactions of interest such as scavenging reactive oxygen species and form products which are specific to the reactions being monitored. Along these lines, we have narrowed on a list of candidate molecules, tested their ability to be polarized, and tested them in vivo. The following molecules have been tested successfully and currently synthetic efforts to scale up synthesis to have adequate quantities for the planned experiments is underway. The following tracers have been synthesized for their ability to participate in the Kreb's cycle: diethyl succinate; monoethyl succinate, a-ketoglutarate. The molecule dimethyl pyrroline N-oxide is a candidate we have successfully synthesized and tested in vivo for use as a reporter of in vivo reactive oxygen species indicator.

a）暴露于放射治疗的荷瘤小鼠中肿瘤pO 2和代谢谱的系列成像：肿瘤微环境的特征在于其独特的生理学和代谢谱，其特征在于由于灌注不良和有氧糖酵解导致的缺氧（低pO 2）和酸中毒（低pH）。这些特征提供了成像生物标志物，如肿瘤pO 2和糖酵解（丙酮酸至乳酸流量），可对其进行监测以评估治疗反应。本研究选择了两种肿瘤模型：C3 H小鼠中的SCCVII肿瘤植入和裸鼠中的HT 29肿瘤。我们首先使用体模对象演示了顺序成像pO 2和糖酵解并将这两个图与解剖图像配准的能力。在此之后，我们基于其不同的肿瘤微环境选择了两种不同的肿瘤模型，并顺序成像了pO 2图和注射的丙酮酸通过糖酵解转化为乳酸的转化，并与解剖图像配准。这使得能够检查肿瘤糖酵解对肿瘤pO 2的依赖性。在所研究的两种肿瘤中，SCCVII肿瘤与HT 29肿瘤相比更糖酵解，这与前者更低氧的性质一致。此外，SCCVII肿瘤中缺氧和糖酵解升高之间存在空间匹配。照射后（5戈伊）分数缺氧增加，这些肿瘤。这通过测量在切除的肿瘤中测量的细胞外酸化速率来支持，并通过监测乳酸盐产生来体外研究。这些研究表明，这两种成像生物标志物可用于计划放射治疗，其中可根据肿瘤pO 2状态的空间特征计划剂量。B）用于超极化MRI的新型13 C标记示踪剂：在体内应用中实施的13 C标记示踪剂中，以下特征是必需的：i）分子在用于体内代谢成像的给药水平下应当是无毒的; ii）其应当具有长T1的碳位点; iii）它应该参与代谢反应或感兴趣的反应，例如清除活性氧物质，并形成对所监测的反应特异的产物。沿着这些路线，我们已经缩小了候选分子的名单，测试了它们的极化能力，并在体内测试了它们。以下分子已经成功地进行了测试，目前正在进行合成努力，以扩大合成规模，使其具有足够的数量用于计划的实验。已经合成了以下示踪剂，用于它们参与克雷布循环的能力：琥珀酸二乙酯;琥珀酸单乙酯，α-酮戊二酸。分子二甲基吡咯啉N-氧化物是一个候选人，我们已经成功地合成和测试在体内用作报告体内活性氧指示剂。