Precision engineering of ultrasonically-targeted drug delivery vehicles

超声靶向给药载体的精密工程

• 批准号: 8036002
• 负责人: Paul A Dayton
• 金额: $ 30.35万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036002
• 关键词: Acoustics; Adverse effects; Analytical Chemistry; Antineoplastic Agents; Area; Balloon Angioplasty; Biochemical; Biodistribution; Biomedical Engineering; Blood; Blood Circulation; Blood Vessels; Book Chapters; Breast Carcinoma; Caliber; California; Carrying Capacities; Characteristics; Clinical; Collaborations; Colon Carcinoma; Contrast Media; Cytotoxic agent; Development; Devices; Disadvantaged; Dose; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Drug resistance; Drug vehicle; Encapsulated; Engineering; FDA approved; Feedback; Focused Ultrasound Therapy; Frequencies; Future; Gases; Goals; Guidelines; Heating; Histology; Human; Image; In Vitro; Industry; Injection of therapeutic agent; Joints; Kaposi Sarcoma; Liposomes; Literature; Location; Magic; Marketing; Mechanics; Mediating; Membrane; Methods; Metric; Microbubbles; Microfluidics; Microscopy; Modeling; Molecular Target; Monitor; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oral Administration; Organ; Ovarian Carcinoma; Paclitaxel; Paper; Pharmaceutical Preparations; Pharmacotherapy; Pharmacy Schools; Physiologic pulse; Principal Investigator; Probability; Process; Production; Property; Public Health; Publications; Publishing; Qualifying; Quality Control; Radiation; Regimen; Research; Research Personnel; Rodent; Rodent Model; Safety; Site; Solubility; Solutions; Specificity; Stents; Stream; Structure; System; Techniques; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Efficacy; Tumor Tissue; Ultrasonic Transducer; Ultrasonics; Ultrasonography; United States National Institutes of Health; Universities; Uterine Fibroids; Walking; Water; base; bone; chemotherapy; clinical application; cremophor EL; density; design; drug distribution; drug testing; effective therapy; experience; fluorophore; improved; in vivo; indexing; interest; intravenous administration; local drug delivery; nanoDroplet; new technology; novel; optical imaging; particle; public health relevance; restenosis; scale up; submicron; success; surface coating; symposium; technology development; tumor

DESCRIPTION (provided by applicant): The development of a "magic bullet" that could carry a therapeutic dose of drug to a target organ or tumor with high specificity is the ideal goal of targeted drug delivery. The development of such a vehicle could improve therapeutic efficacy while reducing side effects. This is of particular interest for chemotherapy administration, where the drugs have high systemic toxicity. In this proposal, novel microfluidic technology is utilized to precision engineer acoustically-active drug delivery vehicles. Currently, liposomes are utilized as one of the most effective drug carriers, although their in-vivo accumulation is relatively non-specific. We propose that by making acoustically-active liposome-like vehicles, we can overcome this nonspecificity by utilizing ultrasound to "steer" the vehicles using acoustic radiation force and then disrupt the vehicle shells to release the contents preferentially at the target site. Acoustically active drug carriers must possess a layer with drug-carrying capacity, similar as a liposome, yet at the same time, they must have a core with significantly different density and compressibility than the surrounding media - such as a gas. Vehicles with this unique multi-layer composition can be created with microfluidics. Additionally, microfluidics provides a precise way to engineer vehicles with exactly the same size, drug payload, and shell characteristics. The uniform acoustic properties of precision engineered vehicles will allow specific tuning of the ultrasound frequency for optimized acoustically-mediated delivery, and will enhance the ability of these vehicles to be used for simultaneous imaging. This proposal describes a multi step process for the development, improvement, and exploration of acoustically-active drug delivery vehicles for site-specific drug delivery. The first step in this proposal is the precision engineering of acoustically active drug delivery vehicles through the application of novel microfluidic technology. The second component consists of testing and optimizing the stability, acoustic properties, and drug release characteristics of these new vehicles, as well as examining the safety of ultrasound parameters optimized to concentrate and disrupt the vehicles. Finally, the delivery potential and biodistribution of the new vehicles will be examined with optical imaging and ultrasound. This collaboration between the principal investigators at the UNC- NCSU Joint Department of Biomedical Engineering, the UNC School of Pharmacy, and the University of California Irvine provide a unique and qualified research group with expertise in ultrasound, microbubbles, drug delivery vehicles and their drug loading and release characteristics, and microfluidics required to achieve these goals. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Our research proposes to create and test new acoustically-active delivery vehicles for site specific delivery of chemotherapeutics. These vehicles have the potential for local delivery of chemotherapy or other drugs while minimizing systemic toxicity. The success of an acoustically localized delivery system would improve therapeutic methods, reduce side effects, and improve public health.

描述（由申请人提供）：开发“魔术子弹”，可以将药物的治疗剂量带到具有高特异性的靶器官或肿瘤是靶向药物的理想目标。这种车辆的发展可以提高治疗功效，同时降低副作用。对于化学疗法给药而言，这尤其令人感兴趣，在该药物中，药物具有较高的全身毒性。在此提案中，新型的微流体技术可用于精确工程师的声学药物输送车辆。目前，脂质体被用作最有效的药物之一，尽管它们的体内积累相对非特异性。我们提出，通过制作声活性脂质体样式车辆，我们可以通过使用声学辐射力来克服这种非特异性，然后使用声学辐射力“引导”车辆，然后破坏车辆壳以优先释放目标位置的内容。声学活性的药物载体必须具有具有药物携带能力的层，与脂质体相似，但与此同时，它们必须具有与周围培养基的密度和可压缩性明显不同的核心，例如气体。具有这种独特的多层组合物的车辆可以使用微流体制作。此外，微流体学提供了一种精确的方法，用于工具具有完全相同的尺寸，有效载荷和外壳特性的车辆。精密工程车辆的均匀声学特性将允许对超声频率进行特定调整，以优化声学介导的传递，并增强这些车辆用于同时成像的能力。该提案描述了用于开发，改进和探索声学药物输送工具的多步骤过程，用于特定地点药物。该提案的第一步是通过应用新型微流体技术的声学活跃药物的精确工程。第二部分包括测试和优化这些新车辆的稳定性，声学特性和药物释放特性，并检查了优化以浓缩和破坏车辆的超声参数的安全性。最后，将使用光学成像和超声检查来检查新车辆的发射潜力和生物分布。 UNC NCSU生物医学工程联合系，UNC药学院和加利福尼亚大学IRVINE联合部门的首席研究人员之间的合作提供了一个独特而合格的研究小组，具有超声，微型物品，药品交付车辆及其药物负载和释放特征以及需要实现这些目标的超声波，药品交付车辆的专业知识。公共卫生相关性：我们的研究叙事旨在创建和测试新的声学活性送货车，以特定于现场的化学治疗剂。这些车辆具有局部化疗或其他药物的潜力，同时最大程度地减少了全身毒性。声学局部递送系统的成功将改善治疗方法，减少副作用并改善公共卫生。