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性剂量的药物携带到高度特异性的靶器官或肿瘤的“魔术子弹”是靶向药物输送的理想目标。这种载体的开发可以提高治疗效果，同时减少副作用。这对于化疗特别有意义，因为这些药物具有很高的全身毒性。在该方案中，利用新型微流控技术对声学活性药物输送载体进行了精密工程设计。目前，脂质体被用作最有效的药物载体之一，尽管它们在体内的蓄积相对来说是非特异性的。我们提出，通过制造具有声学活性的脂质体类载体，我们可以克服这种非特异性，方法是利用超声波利用声辐射力来引导载体，然后破坏载体外壳，在目标位置优先释放内容物。声学活性药物载体必须拥有一层具有载药能力的层，类似于脂质体，但同时，它们必须具有与周围介质(如气体)具有显著不同密度和可压缩性的核心。具有这种独特的多层组成的车辆可以用微流体创造出来。此外，微流体提供了一种精确的方法来设计具有完全相同大小、药物有效载荷和外壳特性的车辆。精密工程车辆的统一声学特性将允许对超声波频率进行特定调整，以优化声学传递，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部位药物输送的声学活性药物输送载体的开发、改进和探索的多步骤过程。这项提议的第一步是通过应用新型微流控技术对声学活性药物输送载体进行精密工程设计。第二部分包括测试和优化这些新载体的稳定性、声学特性和药物释放特性，以及检查为集中和干扰载体而优化的超声波参数的安全性。最后，将通过光学成像和超声波检查新载体的输送潜力和生物分布。北卡罗来纳大学-北卡罗来纳州立大学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这种合作提供了一个独特的、合格的研究小组，他们拥有超声波、微泡、药物输送载体及其药物加载和释放特性以及实现这些目标所需的微流体方面的专业知识。公共卫生相关性：项目叙述我们的研究建议创建和测试新的声学主动输送工具，用于特定地点的化疗药物输送。这些载体有可能在局部输送化疗或其他药物，同时将全身毒性降至最低。声学局部传递系统的成功将改进治疗方法，减少副作用，并改善公共健康。

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.