Treating Tumoral Hypoxia via Ultrasound-Guided Oxygen Release for Improving Radiation Therapy

项目摘要 癌症影响了39.6%的美国人在他们一生中的某个时候。实体瘤微环境是 其特征在于促进低氧区域的紊乱、渗漏的脉管系统。事实上，肿瘤 缺氧是所有放疗、化疗和外科手术治疗效果差的关键预测因子， 也是转移潜能的标志。特别是，肿瘤细胞对放射治疗的抗性增加3倍， 在缺氧细胞和甚至非常小的肿瘤中，包括10-30%的慢性和/或慢性炎症形式的缺氧区域， 短暂性缺氧，在数秒至数天内波动。最近，脂质稳定的氧气微泡 在声动力学治疗中，当直接注射到肿瘤组织中时， 肿瘤，以及显示当腹膜内注射时维持窒息的动物超过两小时。我们 初步数据支持我们的假设，即氧气微泡也可用于缓解肿瘤缺氧 并显著改善治疗效果。此外，没有系统的OMB 到目前为止，OMB用于肿瘤缺氧调节的交付演示，部分原因是难以测量 缺氧在体内可靠地与这些给药组合。我们假设我们可以特别引导 通过超声成像，在肿瘤中优先释放氧，用于放射增敏 显著提高放疗的治愈率。为了验证我们的假设，将优化 微泡制剂和给药参数，评价生物学机制和动力学，以及 在啮齿动物模型中验证我们的假设，然后在两个平移的大型动物模型中验证。 全国领先的兽医学校为了实现这些目标，我们以合作的方式来处理这个项目。 由微泡、氧气输送、放射肿瘤学和肿瘤生物学领域的领先专家组成的团队。

PROJECT SUMMARY Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation. In fact, tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy, chemotherapy and surgery procedures, as well as a hallmark of metastatic potential. In particular, tumor cell resistance to radiotherapy is 3 fold increased in anoxic cells and even very small tumors comprise 10-30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over course of seconds to days. Recently, lipid-stabilized oxygen microbubbles (OMBs) have been used in vivo to relieve tumor hypoxia in sonodynamic therapy when injected directly in the tumors, as well as shown to sustain asphyxiated animals for over two hours when injected intra-peritoneally. Our preliminary data supports our hypothesis that oxygen microbubbles could also be used to relieve tumor hypoxia during radiotherapy and significantly improve treatment outcome. In addition, there has been no systemic OMB delivery demonstration to date for tumor hypoxia modulation with OMBs, due in part to the difficulty of measuring hypoxia in vivo reliably in combination with these administrations. We hypothesize that we can guide specially formulated OMBs via ultrasound imaging, and preferentially release oxygen, in the tumor for radiosensitization to significantly improve the radiotherapy therapeutic ratio. In order to test our hypothesis, will optimize microbubble formulations and administration parameters, evaluate biological mechanisms and kinetics, and validate our hypothesis both in a rodent model and then in a translational large animal model across two of the leading veterinary schools in the country. To achieve these goals, we approach this project with a collaborative team of leading experts in the fields of microbubbles, oxygen transport, radiation oncology, and tumor biology.