Bacteria-Based MR Molecular Imaging of Tumor Oxygenation

描述(申请人提供)：肿瘤氧合在肿瘤生长、侵袭和治疗中起着至关重要的作用。肿瘤组织通常会产生血管内皮生长因子(如血管内皮生长因子)，刺激新生血管的生长，以满足快速生长的肿瘤细胞的高营养需求。肿瘤细胞因其与血管的距离不同而具有不同的特征，并可通过它们的氧合程度来代表：最有活力的细胞是充分灌流和充氧的，低氧细胞是低氧的，而坏死中心含有因缺氧而死亡的细胞。这些肿瘤细胞具有不同的遗传和分子特征，可能对包括放射和化疗在内的各种治疗干预措施有不同的反应。目前，侵入性微电极法是测量肿瘤氧合的金标准。关键是用这种方法选择采样位置，因为当需要围绕同一组织位置进行多个电极测量时可能会产生伪影。我们提出了一种新的分子成像方法来绘制体内肿瘤氧合的地图，该方法基于减毒鼠伤寒沙门氏菌，它选择性地在肿瘤组织中积累和增殖。肌红蛋白将被基因工程改造成沙门氏菌，作为氧气传感器。由于沙门氏菌可以穿透到肿瘤的缺氧区，该方法将给出肿瘤氧合的完整图谱。在这个R21提案中，我们将开发一种新的分子成像方法来映射小鼠肿瘤模型中的肿瘤氧分压，使用减毒鼠伤寒沙门氏菌株过表达氧感应蛋白肌红蛋白。脱氧肌球蛋白可以在体内直接测量，使用质子光谱中-80ppm的特征峰计算氧分压，或在高分辨率肿瘤组织水成像中间接测量，而脱氧肌球蛋白则起到松弛造影剂的作用。这一新的肿瘤氧分压测量将用于观察原发和转移的肿瘤。这些方法将在考虑特定肿瘤微环境中的生理参数的抗癌药物的临床前开发中有大量的应用。由于鼠伤寒沙门氏菌目前处于I期临床试验，该项目可能会对未来原发肿瘤和远处转移的诊断以及治疗规划和癌症临床结果的监测产生重大影响。

DESCRIPTION (provided by applicant): Tumor oxygenation plays a critical important role in tumor growth, invasion, and therapy. Tumor tissues usually produce endothelial growth factors (such as VEGF) that stimulate new growth of blood vessels to meet the high nutrient demands of the fast growing tumor cells. Tumor cells have different characteristics as a function of their distance from the blood vessels and can be typified by their degree of oxygenation: the most viable cells are well perfused and oxygenated, the hypoxic cells are poorly oxygenated, and the necrotic center contain dead cells as a result of oxygen deprivation. These tumor cells have different genetic and molecular characteristics and possibly different response to various therapeutic interventions including radiation and chemotherapy. Currently, invasive microelectrode approach is used as a gold standard measurement of tumor oxygenation. Crucial is the selection of the sampling locations with this method since artifacts may be generated when multiple electrode measurements are required around the same tissue location. We propose a novel molecular imaging approach to map tumor oxygenation in vivo based on an attenuated strain of Salmonella typhimurium that selectively accumulates and proliferate in tumor tissues. Myoglobin will be genetically engineered into the Salmonella bacteria as an oxygen sensor. Since Salmonella can penetrate into the hypoxic areas in the tumor, the method will give a full mapping of tumor oxygenation. In this R21 proposal, we will develop a novel molecular imaging methods to map tumor oxygen tension in murine tumor models using the attenuated Salmonella typhimurium strain that over-expresses the oxygen sensing protein myoglobin. Deoxymyoglobin can be measured directly in vivo using a signature peak at -80 ppm in the proton spectroscopy for oxygen tension calculations, or indirectly in high-resolution tumor tissue water imaging whereas deoxymyoglobin functions as a relaxation contrast reagent. This novel measurement of tumor oxygen tension will be applied to observe the primary and metastasized tumors. The methods will have numerous applications in preclinical development of anticancer drugs considering physiological parameters in a particular tumor microenvironment. Since Salmonella typhimurium is currently in phase I clinical trials, the project may have a major impact in the future diagnosis of both primary tumors and distant metastasis, as well as therapeutic planning and monitoring of the cancer clinical outcomes.