Drug-Loaded Nanobubbles for Ultrasound Enhanced Delivery to Colon Cancer Liver Metastasis

项目摘要 载药纳米气泡超声增强治疗结肠癌肝转移 大多数晚期癌症可以扩散到肝脏，包括乳腺癌、食道癌、胃癌、胰腺癌， 结肠肺肾甚至黑色素瘤肝转移（也称为继发性肝癌）不能 在大多数情况下可以治愈，并且大多数表现为肝转移的患者会死于该疾病。的 问题在结直肠癌中最为突出，在1998年诊断的15万名患者中， 美国每年将最终发展转移性疾病的肝脏由于共享的血液供应 在肠和肝之间。在这个阶段有效的治疗选择是非常有限的，大多数情况下， 接受口服或静脉化疗。接受全身性化疗的患者的中位生存期 化疗仍然只有21个月，主要是由于肿瘤中的低药物吸收，严重的全身毒性和 在肿瘤部位的不均匀药物分布。为了满足对更有效的治疗选择的迫切需要， 肝转移，我们计划开发一种混合治疗诊断纳米泡， 在感兴趣的区域处真实的按需可视且可超声部署。我们激动人心的初赛 数据表明即使在颗粒注射后立即单次施加超声之后， 超声触发的递送导致肿瘤中显著更高的药物浓度， 与游离药物和非触发颗粒相比，在肿瘤内均匀分布。这表明， 特别是在参数优化后，用所提出的构建体治疗肿瘤具有潜力， 最大化肿瘤部位的药物剂量，应该会提高生存率。在本项目范围内，我们 因此，建议优化配方和治疗参数的成功，这种方法。一些 我们的技术与其他技术不同的方面包括：1）研究中使用的纳米颗粒为100-300 nm 但是具有强的超声响应，使得它们在临床相关频率3- 10 Hz下可见。 12 MHz; 2）纳米颗粒具有增强的货物容量，从而能够直接进行简单有效的药物装载 3）可以使用标准脉冲序列用成像换能器触发有效载荷释放 已经可用于临床扫描仪; 4）纳米颗粒是自组装的，因此易于配制和缩放 起来该项目将在四个目标下进行，目标1和2致力于体外表征， 构建体的优化以及评价体内性能的目的3和4。这项工作的最终目标 是开发和优化一种图像引导的药物输送策略， 并导致肿瘤体积内药物分布增强、均匀， 与游离药物相比，最大限度地减少全身蓄积。这项研究的结果将是一个更 改善化疗药物向转移性肝肿瘤递送的有效策略。 影响：我们相信，我们的纳米颗粒的优势和独特方面将使成功的 完成这一目标。这些纳米颗粒将克服药物运输的挑战， 化疗方案用于治疗继发性肝癌的有效性， 把这个研究成果应用到临床上

PROJECT SUMMARY Drug-Loaded Nanobubbles for Ultrasound Enhanced Delivery to Colon Cancer Liver Metastasis Most advanced cancers can spread to the liver including those of the breast, esophagus, stomach, pancreas, colon, lungs, kidneys and even melanoma. Liver metastases (also referred to as secondary liver cancer) cannot be cured in the majority of cases, and most patients presenting with liver metastases will die of the disease. The problem is most pronounced in colorectal cancer, where nearly 85% of the 150,000 patients diagnosed in the United States each year will eventually develop metastatic disease in the liver due to the shared blood supply between the intestine and the liver. Effective treatment options at this stage are severely limited, and most cases are treated with oral or intravenous chemotherapy. The median survival for patients receiving systemic chemotherapy is still only 21 months due primarily to low drug uptake in the tumor, serious systemic toxicity and heterogeneous drug distribution at tumor sites. To meet the urgent need for more effective treatment options for liver metastases, we plan to develop a hybrid theranostic nanobubble which is inherently ultrasound visible and ultrasound-deployable on demand in real time at the region of interest. Our exciting preliminary data demonstrate that even after a single application of ultrasound immediately following particle injection, ultrasound-triggered delivery leads to significantly higher drug concentration in tumors and results in more homogeneous distribution within tumor compared to free drug and non-triggered particles. This suggests that, especially after parameters are optimized, treatment of tumors with the proposed construct has the potential to maximize drug dose at the tumor site and should lead to improved survival. Within the scope of this project we thus propose to optimize formulation and treatment parameters essential to the success of this approach. Some aspects that distinguish our technology from others include 1) nanoparticles used in the study are 100-300 nm in diameter and yet have strong ultrasound response making them visible at clinically relevant frequencies of 3- 12 MHz; 2) nanoparticles have augmented cargo capacity to enable simple and efficient drug loading directly into the particle; 3) payload release can be triggered with the imaging transducer using standard pulse sequences already available on clinical scanners; 4) nanoparticle is self-assembled and thus easily formulated and scaled up. The project will be carried out in four aims with Aims 1 and 2 being dedicated to in vitro characterization and optimization of the construct and Aims 3 and 4 evaluating in vivo performance. The ultimate goal of this work is to develop and optimize an image-guided drug delivery strategy that will maximize drug accumulation in tumors and lead to augmented, homogeneous drug distribution within the tumor volume while minimizing systemic accumulation compared to free drug. The outcome of this research will be a more effective strategy to improve delivery of chemotherapeutic agents to metastatic liver tumors. Impact: We are confident that the advantages and unique aspects of our nanoparticles will enable successful completion of this objective. These nanoparticles will overcome the drug transport challenges and will improve the effectiveness of chemotherapy regimens used in treating secondary liver cancer with ultimate goal to translate this research to the clinic.