Clinically Translatable Ultrasound-Sensitive Microbubble Approaches for Overcoming Tumor Hypoxia

项目总结： 2017年，头颈部鳞状细胞癌(HNSCC)将在美国导致49,700例新病例 全球估计有50万例。在许多情况下，放射是护理的标准。不幸的是，一个 相当大比例的HNSCC也是低氧的，这使得它们对放射治疗的抵抗力明显高于 健康的组织。这种耐药性已被证明削弱了与更高的风险相关的治疗反应 复发和转移。虽然使用全身氧气(O2)输送的方法在很大程度上已经停滞不前，但我们的 该小组已经在乳腺癌模型中显示出在肿瘤控制和生存方面的实质性改善 超声敏感、基于表面活性物质的O2微泡平台可立即克服肿瘤缺氧 到放射治疗。在静脉注射后，可以使用超声波无创地破裂气泡， 触发局部肿瘤内氧气的释放。虽然这个平台很有希望，但临床翻译还没有 氧合时间限制在2-3分钟是可行的。我们的假设是，我们可以使用 用氯硝胺和二甲双胍(两种药物)联合用氧治疗 主要通过线粒体呼吸选择性地靶向肿瘤的代谢途径)。我们期待着 这些药物的加入将延长氧合时间，同时还可以改善全身抗肿瘤免疫反应 (通过非局域效应)，并将治疗效果从原发肿瘤扩展到转移性疾病。 建议的工作在逻辑上分为三个逻辑目标，每个目标都有足够的支持 初步数据不要求在任何目标上相互依赖。在目标1中，我们将修改以前的设计 还可以包裹洛尼达明(其生物利用度限制了临床翻译)。微泡将会是 经过优化，最大限度地提高稳定性和有效载荷，然后在低氧条件下进行声学特性和验证 细胞培养。目标2将包括口服和不口服二甲双胍的体内氧气监测实验 比较以前的氧气微泡设计和对照，以确定最佳的放射治疗 参数和临床可行性。还将进行生物分布研究，以评估当地递送的 浪尼达胺。最后，在AIM 3中，平台和选定的定时和声学参数将在体内进行验证 在荷瘤小鼠中使用已建立的和特征良好的HNSCC模型。我们将确定是否有能力 使用O2微泡有效地增强肿瘤对辐射的敏感性(通过肿瘤生长动力学和效应进行评估 生存)，同时也探索该平台在增强肿瘤免疫反应方面的作用 免疫功能正常小鼠的微环境。在这个项目结束时，我们将开发和 验证了一种微创和临床可翻译的方法，以克服肿瘤缺氧之前 放射治疗。我们预计该平台将通过改善对以下方面的反应来改善患者的预后 放射治疗并有可能降低治疗后HNSCC复发和转移的发生率。

Project Summary: In 2017 head and neck squamous cell carcinoma (HNSCC) will result in 49,700 new cases in the United States and an estimated 500,000 cases worldwide. Radiation is standard of care in many cases. Unfortunately, a significant percentage of HNSCCs are also hypoxic, making them markedly more resistant to radiotherapy than healthy tissue. This resistance has been shown to impair treatment response associated with a higher risk of recurrence and metastasis. While approaches using systemic oxygen (O2) delivery have largely stalled, our group has shown substantial improvements in tumor control and survival in breast cancer models using an ultrasound sensitive, surfactant-based O2 microbubble platform to overcome tumor hypoxia immediately prior to radiotherapy. After intravenous injection, ultrasound can be used to noninvasively rupture the bubbles, triggering a localized intratumoral release of O2. While promising, clinical translation of this platform is not yet feasible as oxygenation is limited to 2-3 minutes. Our hypothesis is we can overcome these limitations using a combination therapy of oxygen delivery with lonidamine and metformin (two pharmaceutical agents that selectively target the metabolic pathway in tumors primarily by mitochondrial respiration). We expect the addition of these agents will prolong oxygenation while also improving systemic anti-tumor immune responses (via the abscopal effect) and extend therapeutic effects beyond the primary tumor to metastatic disease. The proposed work is logically divided into three logical aims each of which is supported by sufficient preliminary data to not require inter-dependence across any aims. In Aim 1 we will modify our previous design to also encapsulate lonidamine (whose bioavailability has limited clinical translation). Microbubbles will be optimized to maximize stability and payload before being acoustically characterized and validated in hypoxic cell culture. Aim 2 will comprise of in vivo O2 monitoring experiments with and without oral metformin to compare previous O2 microbubble designs and controls in order to define optimal radiotherapy treatment parameters and clinical feasibility. Biodistribution studies will also be performed to evaluate local delivery of lonidamine. Finally, in Aim 3, the platform and selected timing and acoustic parameters will be validated in vivo in tumor-bearing mice using established and well-characterized HNSCC models. We will determine the ability of O2 microbubbles to effectively sensitize tumors to radiation (evaluated by tumor growth kinetics and effects on survival), while also exploring the platform's effects on increased immune response in the tumor microenvironment in immunocompetent mice. At the conclusion of this project, we will have developed and validated a minimally invasive and clinically translatable method to overcome tumor hypoxia prior to radiotherapy. We expect that this platform will improve patient outcomes by improving responses to radiotherapy and potentially reduce the prevalence of recurrence and metastasis of HNSCC after treatment.