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

项目总结 39.6%的美国人一生中都会患上癌症。实体肿瘤微环境是 以无组织的、渗漏的血管系统为特征的，促进低氧区域。事实上，肿瘤 低氧是所有放疗、化疗和外科手术治疗结果不佳的关键预测因素， 也是转移潜能的标志。特别是，肿瘤细胞对放射治疗的抵抗力增加了3倍 在缺氧细胞甚至非常小的肿瘤中，10%-30%的缺氧区以慢性和/或 一过性低氧在几秒钟到几天的过程中波动。最近，脂质稳定的氧气微泡 (OMBs)已在体内用于声动力疗法中，当直接注射到肿瘤组织中时，缓解肿瘤缺氧 肿瘤，以及显示维持窒息动物超过两个小时，当注射在腹膜内。我们的 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 在放射治疗期间，显著改善治疗结果。此外，还没有系统性的管理和预算办公室 到目前为止，利用OMBs进行肿瘤缺氧调节的交付演示，部分原因是测量困难 体内缺氧与上述给药联合给药可靠。我们假设我们可以特别指导 通过超声成像形成OMBs，并优先在肿瘤内释放氧气进行放射增敏 以显著提高放射治疗的比率。为了检验我们的假设，我们将优化 微泡制剂和给药参数，评估生物机制和动力学，以及 在啮齿动物模型中验证我们的假设，然后在转换的大型动物模型中验证我们的假设 全国领先的兽医学校。为了实现这些目标，我们以协作的方式处理此项目 由微泡、氧气运输、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.