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

用于超声增强递送至结肠癌肝转移的载药纳米气泡

• 批准号: 10696225
• 负责人: Agata A Exner
• 金额: $ 46.31万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696225
• 关键词: Address; Advanced Malignant Neoplasm; Antineoplastic Agents; Area; Biodistribution; Blood Cells; Blood Vessels; Breast; Cell Culture Techniques; Cell Wall; Cell model; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; Complex; Contrast Media; Data; Dedications; Diagnosis; Diameter; Disease; Dose; Dose Limiting; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Drug Transport; Effectiveness; Engineering; Equipment; Esophagus; Excision; Extravasation; Formulation; Frequencies; Gases; Goals; HCT116 Cells; Human; Hybrids; Image; In Vitro; Injections; Intestines; Intravenous; Kidney; LS174T colon cancer cell line; Large Intestine Carcinoma; Lipids; Liposomes; Liver; Lung; Measures; Mediating; Metastatic Neoplasm to the Liver; Micelles; Microbubbles; Modeling; Mus; Nanotechnology; Oral; Organ; Outcome; Outcomes Research; Pancreas; Patients; Penetration; Performance; Permeability; Pharmaceutical Preparations; Physiologic pulse; Play; Polymers; Predisposition; Research; Research Support; Role; Signal Transduction; Site; Solid Neoplasm; Stomach; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Transducers; Translating; Treatment Efficacy; Treatment outcome; Tumor Tissue; Tumor Volume; United States; Vascular blood supply; Visualization; Work; cancer cell; cancer diagnosis; cell killing; chemosensitizing agent; chemotherapeutic agent; chemotherapy; clinical imaging; clinically relevant; colon cancer patients; colorectal cancer metastasis; delivery vehicle; design; drug distribution; drug efficacy; effective therapy; image-guided drug delivery; imaging properties; improved; in vivo; interest; melanoma; metastatic colorectal; meter; nanobubble; nanoparticle; neoplastic cell; particle; response; scale up; self assembly; success; systemic toxicity; theranostics; time use; treatment strategy; tumor; tumor growth; tumor heterogeneity; tumor microenvironment; ultrasound; uptake

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.

项目摘要 吸毒的纳米泡超声增强了结肠癌肝转移的递送 大多数晚期癌症都可以传播到肝脏，包括乳房，食道，胃，胰腺， 结肠，肺，肾脏甚至黑色素瘤。肝转移（也称为继发性肝癌）不能 在大多数病例中治愈，大多数患有肝转移的患者将死于该疾病。这 问题在结直肠癌中最为明显，在该癌症中，有近85％的患者中有85％ 由于共享血液供应 在肠道和肝脏之间。在此阶段有效的治疗选择受到严重限制，大多数情况 用口服或静脉化疗治疗。接受全身患者的中位生存期 化学疗法仍然仅是21个月，主要是由于肿瘤中药物摄取低，严重的全身毒性和 肿瘤部位的异质药物分布。满足迫切需要对更有效的治疗选择 肝转移，我们计划开发一种固有超声的混合疗法纳米泡 可见的和超声检查可在感兴趣的地区实时按需进行。我们令人兴奋的初步 数据表明，即使在颗粒注射后立即使用超声检查后， 超声触发的递送导致肿瘤的药物浓度明显更高，并导致更多 与游离药物和非触发颗粒相比，肿瘤内的均匀分布。这表明， 特别是在优化参数之后，用拟议构建体对肿瘤的处理有可能 在肿瘤部位最大化药物剂量，应提高生存率。在这个项目的范围内我们 因此，建议优化对该方法成功必不可少的配方和治疗参数。一些 区分我们技术与其他技术的方面包括1）研究中使用的纳米颗粒为100-300 nm 直径且具有强大的超声反应，使其在3--的临床相关频率下可见 12 MHz; 2）纳米颗粒具有增强的货物能力，可直接实现简单有效的药物加载 进入粒子； 3）可以使用标准脉冲序列使用成像传感器触发有效载荷释放 已经在临床扫描仪上可用； 4）纳米颗粒是自组装的，因此很容易配制和缩放 向上。该项目将以四个目标进行，目标1和2用于体外表征和 构建体的优化和目标3和4评估体内性能。这项工作的最终目标 是开发和优化图像引导的药物输送策略，该策略将最大化药物积累 在肿瘤中，导致肿瘤体积内增强，均质药物分布 与自由药物相比，最小化全身积累。这项研究的结果将是更多 改善化学治疗剂向转移性肝肿瘤的递送的有效策略。 影响：我们相信，纳米颗粒的优势和独特方面将使成功 完成此目标。这些纳米颗粒将克服药物运输挑战，并将改善 用于治疗继发性肝癌的化学疗法方案的有效性，最终目标是 将这项研究转化为诊所。