Oxygen Microbubbles for Overcoming Hypoxic Tumor Resistance to Radiotherapy

氧气微泡克服缺氧肿瘤对放射治疗的抵抗力

• 批准号: 8959408
• 负责人: John Eisenbrey
• 金额: $ 21.77万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-23 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959408
• 关键词: Acoustics; Aftercare; Animals; Apoptosis; Blood Circulation; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Caliber; Carbogen Breathing; Cell Culture Techniques; Clinical; Contrast Media; Diagnostic Neoplasm Staging; Diffusion; External Beam Radiation Therapy; Frequencies; Gases; Half-Life; Hemoglobin; Histology; Human; Hypoxia; In Vitro; Infusion procedures; Injectable; Injection of therapeutic agent; Malignant Neoplasms; Mammary Neoplasms; Measures; Methods; Microbubbles; Modeling; Monitor; Mus; Nature; Needles; Neoplasm Metastasis; Nitrogen; Operative Surgical Procedures; Outcome; Oxygen; Patients; Prevalence; Primary Neoplasm; Radiation; Radiation therapy; Recurrence; Relative (related person); Resistance; Rupture; Solid Neoplasm; Solutions; Staging; Techniques; Time; Tissues; Translating; Tumor Oxygenation; Ultrasonography; Xenograft procedure; acoustic imaging; attenuation; base; cancer therapy; capillary bed; chemotherapy; high reward; high risk; hyperbaric chamber; improved; in vivo; malignant breast neoplasm; minimally invasive; multidisciplinary; oxygen transport; photoacoustic imaging; pressure; prevent; public health relevance; radiation resistance; reconstitution; research study; response; sensor; surfactant; treatment response; tumor; tumor xenograft

 DESCRIPTION (provided by applicant): Focused radiation therapy is frequently used in the treatment of cancer both to eradicate the primary tumor and to prevent and treat metastasis. Unfortunately, many tumors are hypoxic, which increases their resistance to radiotherapy, resulting in decreased treatment response as well as a higher likelihood of recurrence and metastasis. Thus, a technique that could locally increase tumor oxygen levels immediately prior to radiation therapy is expected to significantly improve patient outcomes. We propose to develop and optimize an injectable, ultrasound sensitive oxygen-filled microbubble platform for overcoming tumor hypoxia immediately prior to radiotherapy. The main hypothesis of this project is that directed ultrasound-triggered destruction of oxygen-filled microbubbles can be used to elevate tumor oxygenation levels immediately prior to radiotherapy and that this sensitization will significantly improve treatment response. The first portion of this project wil be to optimize and characterize surfactant shelled oxygen-filled microbubbles in vitro for maximum tumor oxygenation. Parameters such as stability, size, concentration, and shell composition will all be characterized and optimized to provide maximum oxygen delivery. Acoustic triggering parameters will also be investigated to maximize localized microbubble destruction. In vitro experiments will be performed to determine the ability of the platform to sensitize cell cultures t radiation. Finally, the platform and selected acoustic parameters will be used in an in vitro setup to characterize the microbubble's ability to locally elevate oxygen concentrations in solution. The second portion of this project will be to validate the platform's ability to elevate tumoral oxygen levels in a mouse tumor model. Selected acoustic parameters will be translated to a commercial ultrasound scanner and used to locally trigger microbubble destruction in vivo. Changes in the tumor oxygenation levels will then be monitored using noninvasive photo-acoustic imaging and invasive needle-based oxygen probes and compared to non-triggered or nitrogen-filled microbubble controls. The final portion of this project will then be to determine the platform's ability to sensitize the selected tumor model to radiation therapy. The platform will be used to increase tumor oxygenation levels immediately prior to radiation therapy. Tumor response will then be evaluated based on size, histology, and animal survival, and compared to respective controls. Tumor hypoxia-associated radiation resistance is a major unmet challenge to improving therapy. This application proposes a multidisciplinary, high-risk/high reward solution to this clinical imperative, which will improve patient outcomes by improving tumoral response to radiotherapy and potentially reduce the prevalence of recurrence and metastasis after treatment. At the conclusion of this project, we expect to have developed and validated a minimally invasive method for overcoming tumor hypoxia prior to radiotherapy.

 描述（由申请人提供）：聚焦放射疗法经常用于治疗癌症，以根除原发性肿瘤并预防和治疗转移。不幸的是，许多肿瘤是缺氧的，这增加了它们对放射治疗的抵抗力，导致治疗反应降低以及复发和转移的可能性更高。因此，一种可以在放射治疗前立即局部增加肿瘤氧水平的技术有望显著改善患者的预后。我们建议开发和优化一种可注射的超声敏感充氧微泡平台，用于在放疗前立即克服肿瘤缺氧。该项目的主要假设是，定向超声触发的充满氧气的微泡的破坏可用于在放疗前即刻提高肿瘤氧合水平，并且这种敏化将显著改善治疗反应。 本项目的第一部分将是优化和表征表面活性剂壳充氧微泡体外最大肿瘤氧合。稳定性、尺寸、浓度和外壳成分等参数都将进行表征和优化，以提供最大的氧气输送。还将研究声触发参数，以最大限度地破坏局部微泡。将进行体外实验以确定平台使细胞培养物对辐射敏感的能力。最后，将在体外设置中使用平台和选定的声学参数 以表征微泡局部提高溶液中氧浓度的能力。的 该项目的第二部分将验证该平台提高肿瘤氧含量的能力 在小鼠肿瘤模型中的水平。选定的声学参数将被转换到商业超声扫描仪，并用于在体内局部触发微泡破坏。然后使用非侵入性光声成像和侵入性针基氧探头监测肿瘤氧合水平的变化，并与非触发或氮气填充的微泡对照进行比较。该项目的最后一部分将是确定该平台使所选肿瘤模型对放射治疗敏感的能力。该平台将用于在放射治疗前即刻增加肿瘤氧合水平。然后根据大小、组织学和动物存活率评价肿瘤缓解，并与相应对照组进行比较。 肿瘤缺氧相关的辐射抗性是改善治疗的主要未满足的挑战。该申请提出了一种多学科、高风险/高回报的解决方案来应对这一临床需求，这将通过改善肿瘤对放疗的反应来改善患者结局，并可能降低治疗后复发和转移的发生率。在该项目结束时，我们希望开发并验证一种微创方法，用于在放疗前克服肿瘤缺氧。