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

通过超声引导释氧治疗肿瘤缺氧以改善放射治疗

• 批准号: 10163814
• 负责人: Paul A Dayton
• 金额: $ 13.93万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163814
• 关键词: Affect; American; Anesthesia procedures; Animal Hospitals; Animal Model; Animals; Biological; Biological Markers; Blood Circulation; Canis familiaris; Carbogen; Cells; Chronic; Client; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Country; Data; Development; Devices; Disease; Dose; Endothelium; Environment; Formulation; Free Radicals; Goals; Histology; Hour; Human; Hyperbaric Oxygenation; Hypoxia; Inhalation; Injections; Intravenous; Kinetics; Lipids; Literature; Long-Term Effects; Malignant Neoplasms; Measurement; Measures; Microbubbles; Modeling; Nitrogen; Nitroimidazoles; Normal tissue morphology; Operative Surgical Procedures; Oxidative Stress; Oxygen; Oxygen Therapy Care; Patients; Peritoneal; Physiologic pulse; Procedures; Protocols documentation; Public Health; Radiation Oncology; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Rattus; Resistance; Rodent Model; Route; Signal Transduction; Site; Soft tissue sarcoma; Solid Neoplasm; Sonication; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; Treatment outcome; Tumor Biology; Tumor Oxygenation; Tumor Tissue; Ultrasonography; Validation; Vascularization; Veterinary Schools; Work; biomaterial compatibility; cancer cell; chemotherapy; clinical translation; dosage; efficacy evaluation; fibrosarcoma; hypoxia inducible factor 1; image guided; improved; in vivo; intravenous administration; neoplastic cell; novel; oxygen transport; radiation resistance; radioresistant; real time monitoring; response; symposium; technology development; therapy outcome; tumor; tumor hypoxia; tumor microenvironment; vasoconstriction

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.

项目概要 39.6% 的美国人在一生中的某个阶段会受到癌症的影响。实体瘤微环境是 其特点是脉管系统紊乱、渗漏，导致低氧合作用区域。事实上，肿瘤 缺氧是所有放疗、化疗和手术过程中治疗效果不佳的一个关键预测因素， 以及转移潜力的标志。特别是肿瘤细胞对放疗的抵抗力增加了3倍 在缺氧细胞中，甚至非常小的肿瘤也包含 10-30% 的慢性缺氧区域和/或 短暂缺氧在几秒到几天内波动。最近，脂质稳定氧微泡 (OMB) 已在体内用于在声动力疗法中直接注射到体内以缓解肿瘤缺氧。 腹膜内注射时，可以使窒息的动物维持两个多小时。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，显着改善治疗效果。此外，还没有系统性的OMB 迄今为止，通过 OMB 进行肿瘤缺氧调节的交付演示，部分原因是测量困难 与这些给药相结合，可以可靠地抑制体内缺氧。我们假设我们可以专门指导 通过超声成像配制 OMB，并优先释放氧气，在肿瘤中实现放射增敏 显着提高放疗治疗比。为了检验我们的假设，将优化 微泡配方和给药参数，评估生物机制和动力学，以及 在啮齿动物模型和跨两个动物的转化大型动物模型中验证我们的假设 国内领先的兽医学校。为了实现这些目标，我们通过协作来完成该项目 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。