Precision engineering of ultrasonically-targeted drug delivery vehicles

描述（由申请人提供）：开发一种能够将治疗剂量的药物以高特异性携带到目标器官或肿瘤的“神奇子弹”是靶向给药的理想目标。这种载体的开发可以提高治疗效果，同时减少副作用。这对化疗药物的管理特别有意义，因为化疗药物具有很高的全身毒性。在这个提议中，新的微流体技术被用于精密工程声活性药物输送车辆。目前，脂质体被用作最有效的药物载体之一，尽管它们在体内的积累相对不具有特异性。我们提出，通过制造声活性脂质体样载体，我们可以克服这种非特异性，利用超声利用声辐射力“操纵”载体，然后破坏载体外壳，使其优先在目标部位释放内容物。声活性药物载体必须具有一层类似于脂质体的载药能力，但同时，它们必须具有一个密度和可压缩性与周围介质（如气体）明显不同的核心。具有这种独特多层成分的车辆可以用微流体制造。此外，微流体提供了一种精确的方法来设计具有完全相同尺寸，药物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谐，以优化声学介导的传输，并将增强这些车辆用于同时成像的能力。本提案描述了用于特定位点药物递送的声活性药物递送载体的开发、改进和探索的多步骤过程。本方案的第一步是通过应用新型微流体技术进行声活性药物运载工具的精密工程。第二部分包括测试和优化这些新型车辆的稳定性、声学特性和药物释放特性，以及检查优化后的超声参数的安全性，以集中和干扰车辆。最后，将利用光学成像和超声检查新型运载工具的运载潜力和生物分布。北卡罗来纳大学- NCSU生物医学工程联合系、北卡罗来纳大学药学院和加州大学欧文分校的主要研究人员之间的合作，提供了一个独特而合格的研究小组，他们在超声、微泡、药物输送载体及其药物装载和释放特性以及实现这些目标所需的微流体方面具有专业知识。我们的研究建议创造和测试新的声学活性运载工具，用于特定部位的化疗药物输送。这些运载工具具有局部递送化疗或其他药物的潜力，同时将全身毒性降到最低。声学定位递送系统的成功将改进治疗方法，减少副作用，并改善公众健康。

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.