Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

a)放射治疗荷瘤小鼠肿瘤pO2和代谢谱的序列成像：肿瘤微环境具有独特的生理和代谢谱，其特征是缺氧（低pO2）和酸中毒（低pH），这是由于灌注不良和有氧糖酵解所致。这些特征提供了成像生物标志物，如肿瘤pO2和糖酵解（丙酮酸到乳酸的流量），可以监测以评估治疗反应。本研究选择两种肿瘤模型：C3H小鼠移植的SCCVII肿瘤和裸鼠HT29肿瘤。我们首先使用幻影对象演示了顺序成像pO2和糖酵解的能力，并将这两个地图与解剖图像共同注册。在此之后，我们根据不同的肿瘤微环境选择了两种不同的肿瘤模型，并依次对pO2图谱和注射的丙酮酸盐通过糖酵解转化为乳酸盐进行成像，并与解剖图像共同注册。这使得检测肿瘤糖酵解对肿瘤pO2的依赖性成为可能。在研究的两种肿瘤中，SCCVII肿瘤比HT29肿瘤更具糖酵解性，这与前者更低氧的性质一致。此外，在SCCVII肿瘤中，缺氧与糖酵解升高之间存在空间匹配。照射（5 Gy）后，这些肿瘤的缺氧程度增加。通过测量切除肿瘤的细胞外酸化率并在体外监测乳酸生成来研究，这一点得到了支持。这些研究表明，这两种成像生物标志物可以用于规划放射治疗，其中剂量可以根据肿瘤pO2状态的空间特征来计划。b)用于超极化MRI的新型13C标记示踪剂：在体内应用中，13C标记示踪剂必须具备以下特征：i)分子在体内代谢成像中施用的水平下应该是无毒的；ii)有一个长T1的碳位；iii)应参与代谢反应或感兴趣的反应，如清除活性氧，并形成特定于被监测反应的产物。沿着这些思路，我们缩小了候选分子的范围，测试了它们的极化能力，并在体内进行了测试。以下分子已成功测试，目前正在努力扩大合成规模，以获得足够数量的计划实验。以下示踪剂因其参与克雷布斯循环的能力而被合成：琥珀酸二乙酯；琥珀酸一乙酯，a-酮戊二酸酯。二甲基吡咯啉n -氧化物是我们已经成功合成并在体内测试的候选分子，可以作为体内活性氧的报告因子。

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.