Precision engineering of ultrasonically-targeted drug delivery vehicles

描述（由申请人提供）：开发一种能够以高特异性将治疗剂量的药物携带到靶器官或肿瘤的“魔术子弹”是靶向药物递送的理想目标。这种载体的开发可以提高治疗效果，同时减少副作用。这对于化疗施用是特别感兴趣的，其中药物具有高全身毒性。在这个建议中，新的微流体技术被用来精确工程声学活性药物输送车辆。目前，脂质体被用作最有效的药物载体之一，尽管它们的体内积累相对非特异性。我们建议，通过制作声学活性脂质体样车辆，我们可以克服这种非特异性，利用超声“转向”车辆使用声辐射力，然后破坏车辆外壳，优先在目标部位释放内容物。声学活性药物载体必须具有与脂质体类似的具有载药能力的层，但同时，它们必须具有与周围介质（例如气体）显著不同的密度和可压缩性的核心。具有这种独特的多层组合物的载体可以用微流体来制造。此外，微流体技术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征的车辆。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，以优化声学介导的递送，并将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、改进和探索用于位点特异性药物递送的声学活性药物递送载体的多步骤过程。该提案的第一步是通过应用新型微流体技术对声学活性药物递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，以及检查优化的超声参数的安全性，以集中和破坏载体。最后，将用光学成像和超声波检查新载体的输送潜力和生物分布。在生物医学工程，药学院，和加州尔湾大学的联合部的主要研究者之间的这种合作提供了一个独特的和合格的研究小组，在超声，微泡，药物输送车辆和他们的药物装载和释放特性的专业知识，以及实现这些目标所需的微流体。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车辆的化疗药物的网站特定的交付。这些载体具有局部递送化疗或其他药物的潜力，同时使全身毒性最小化。声学定位输送系统的成功将改善治疗方法，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.