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

项目总结 载药纳米泡超声增强治疗结肠癌肝转移的实验研究 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 在大多数病例中被治愈，大多数出现肝转移的患者将死于这种疾病。这个 问题在结直肠癌中最为明显，在15万名被诊断为结直肠癌的患者中，近85%的人 由于共享的血液供应，美国每年都会最终发展为肝脏转移疾病 在肠道和肝脏之间。在这个阶段，有效的治疗选择严重有限，大多数病例 接受口服或静脉化疗。接受全身化疗的患者的中位生存期 化疗仍然只有21个月，主要原因是肿瘤的药物摄取率低，严重的全身毒性和 肿瘤部位药物分布不均。以满足对更有效的治疗方案的迫切需求 为了治疗肝转移，我们计划开发一种混合型超声纳米气泡。 可视和超声波-可在感兴趣区域按需实时部署。我们激动人心的预赛 数据表明，即使在颗粒注射后立即单次应用超声波， 超声触发递送导致肿瘤中显著更高的药物浓度并导致更多 与游离药物和非触发颗粒相比，在肿瘤内的均匀分布。这表明， 特别是在参数优化后，使用所提议的构造治疗肿瘤具有潜在的 最大限度地增加肿瘤部位的药物剂量，并应导致提高存活率。在这个项目的范围内，我们 因此，建议优化配方和治疗参数，这对这一方法的成功至关重要。一些人 我们的技术与其他技术的不同之处包括：1)研究中使用的纳米颗粒为100-300纳米 直径大，但具有强烈的超声反应，使它们在临床上相关的频率3- 12 MHz；2)纳米颗粒增加了载货能力，使直接装载药物变得简单而有效 3)有效载荷释放可以通过使用标准脉冲序列的成像换能器来触发 已在临床扫描仪上使用；4)纳米颗粒是自组装的，因此很容易配制和缩放 向上。该项目将在四个目标中进行，目标1和目标2致力于体外鉴定和 优化构建，并对目标3和4进行体内评价。这项工作的最终目标是 是开发和优化一种图像引导的药物输送策略，使药物积累最大化 并导致增大的、均匀的药物分布在肿瘤体积内，而 与免费药物相比，最大限度地减少全身蓄积。这项研究的结果将是更多的 改善转移性肝肿瘤化疗药物输送的有效策略。 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 完成这一目标。这些纳米粒子将克服药物运输方面的挑战，并将改善 化疗方案治疗继发性肝癌的疗效观察 将这项研究转化为临床研究。

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.