Clinically Translatable Ultrasound-Sensitive Microbubble Approaches for Overcoming Tumor Hypoxia

项目摘要： 2017年，头颈部鳞状细胞癌（HNSCC）将导致美国49，700例新发病例 全球估计有50万例在许多情况下，放射治疗是治疗的标准。不幸的是 相当大比例的HNSCC也是缺氧的，使得它们对放射治疗的抵抗力明显高于对照组。 健康组织这种耐药性已被证明会损害治疗反应，与更高的风险相关。 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，但我们的 研究小组在乳腺癌模型中显示了肿瘤控制和生存的实质性改善， 超声敏感、基于表面活性剂的O2微泡平台，可在肿瘤缺氧前立即克服 到放疗。静脉注射后，超声可用于非侵入性地破裂气泡， 引发局部肿瘤内氧气释放虽然前景看好，但该平台的临床转化尚未实现。 因为氧合限于2 - 3分钟。我们的假设是，我们可以克服这些限制， 氧输送与氯尼达明和二甲双胍（两种药剂， 主要通过线粒体呼吸选择性靶向肿瘤中的代谢途径）。我们预计 这些药剂的添加将延长氧合，同时还改善全身抗肿瘤免疫应答 (via远位效应）并将治疗效果扩展到原发性肿瘤以外的转移性疾病。 拟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。 初步数据不需要任何目标之间的相互依赖。在目标1中，我们将修改我们以前的设计 还包封氯尼达明（其生物利用度限制了临床转化）。微泡将 优化以最大化稳定性和有效载荷，然后在低氧环境中进行声学表征和验证 细胞培养目标2将包括有和没有口服二甲双胍的体内O2监测实验， 比较先前的O2微泡设计和对照，以确定最佳放射治疗 参数和临床可行性。还将进行生物分布研究，以评价局部递送 氯尼达明最后，在目标3中，将在体内验证平台和选定的时序和声学参数 在荷瘤小鼠中使用建立的和充分表征的HNSCC模型。我们将确定 的O2微泡，以有效地使肿瘤对辐射敏感（通过肿瘤生长动力学和效应评估 同时还探索了该平台对肿瘤中免疫反应增加的影响 免疫活性小鼠的微环境。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转化的方法，以克服肿瘤缺氧之前， 放疗我们预计，该平台将通过改善对以下问题的反应来改善患者的治疗结果： 放疗和潜在地降低治疗后HNSCC的复发和转移的患病率。

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.