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

基本信息

批准号：
10402933
负责人：
Paul A Dayton
金额：
$ 56.03万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10402933
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 ultrasound vasoconstriction

项目摘要

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.

项目摘要癌症在一生中的某个时候影响了39.6％的美国人。实体瘤微环境是其特征是散布的，漏水的脉管系统，可促进低氧化区域。实际上，肿瘤缺氧是所有放射疗法，化学疗法和手术程序的治疗结果不良的关键预测因子，以及转移潜力的标志。特别是，肿瘤细胞对放射疗法的耐药性增加了3倍在缺氧细胞，甚至很小的肿瘤中，以慢性和/或形式占低氧区域的10-30％短暂的缺氧在几秒钟到几天内波动。最近，脂肪稳定的氧微泡（OMB）已在体内使用，以减轻直接注射在声动力疗法中的肿瘤缺氧肿瘤，以及显示在腹膜内注射窒息的动物两个多小时以上的肿瘤。我们的初步数据支持我们的假设，即氧微泡也可用于缓解肿瘤缺氧在放疗过程中，并显着改善了治疗结果。此外，没有系统性的OMB 迄今为止，肿瘤缺氧调节的送达示范，部分原因是难以测量体内缺氧可靠地结合这些管理。我们假设我们可以特别指导通过超声成像制定的OMB，并优先释放氧气，以进行放射敏化显着提高放射疗法的治疗比率。为了检验我们的假设，将优化微泡制剂和给药参数，评估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该国领先的兽医学校。为了实现这些目标，我们通过协作来实现该项目微泡，氧运输，辐射肿瘤学和肿瘤生物学领域的领先专家团队。