Continuous-Flow Microfluidic Nanomanufacturing of Nanomedicines

纳米粒子使能药物在改善人类健康方面具有巨大的潜力，使药物设计者能够定制治疗化合物向特定组织或细胞的递送，并优化药物进入这些细胞的吸收。特别地，使用脂质囊泡或脂质体作为纳米级药物载体已经导致了对一系列癌症的治疗的显著进展。然而，脂质体纳米药物从实验室到临床的过渡仍然受到缺乏能够在整个生产范围内扩展的纳米制造方法的限制。该奖项将研究连续流微流体技术，作为弥合这一差距的独特可扩展方法。该技术将在连续流微流体系统中利用多个尺寸尺度的化学和物理现象，从而实现纳米颗粒自组装、被动和主动载药、纳米颗粒功能化以及药物纯化和浓缩。将开发和优化单个流体模块，并将连续模块组合在一个连续流动的纳米工厂中。该多学科项目将整合高中生通过研究生研究人员的贡献，并导致开发一种新的纳米药物，用于治疗复发性小儿神经母细胞瘤，这是一种临床结果令人沮丧的高风险癌症。目前的脂质体药物合成技术必须在每个生产规模进行重新设计，引入了制造成本和工程挑战，这对新脂质体药物的开发构成了重大障碍。克服这一差距从根本上说是一个纳米制造的挑战。我们将开发一种多级微流体流动聚焦技术，作为一种高度可扩展的方法，支持在连续流动过程中全面生产脂质体纳米药物。这些研究将为每个处理阶段的基础多尺度物理产生新的见解，从而提高对微流体系统内脂质体自组装，药物装载和靶向剂附着所涉及的化学物理过程的理解。这项工作还将为与耦合不同的连续流微流体模块用于先进的功能化纳米颗粒制造相关的关键工程挑战提供新的解决方案。该技术的性能将使用一种新的纳米医学测试平台进行评估。具体而言，该奖项将展示一种靶向多药，包括两亲性化疗药物（阿霉素）和亲脂性酪氨酸激酶抑制剂（厄洛替尼），用于治疗小儿神经母细胞瘤。使用这个试验台，将探索规模扩大和规模缩小的组合，为多规模脂质体药物合成提供统一的框架，大大提高了速度，降低了纳米药物制造的复杂性。

Nanoparticle-enabled drugs hold enormous potential for improving human health, allowing drug designers to tailor the delivery of therapeutic compounds to specific tissues or cells, and optimize the uptake of drugs into those cells. In particular, the use of lipid vesicles or liposomes as nanoscale drug carriers has resulted in significant advances toward the treatment of a range of cancers. However, the transition of liposomal nanomedicines from the lab to the clinic remains constrained by the lack of nanomanufacturing methods capable of scaling across the full production range. This award will investigate continuous-flow microfluidics technology as a unique scalable approach to bridge this gap. This technology will leverage chemical and physical phenomena across multiple size scales within a continuous-flow microfluidic system, resulting in nanoparticle self-assembly, passive and active drug loading, nanoparticle functionalization, and drug purification and concentration. Individual fluidic modules will be developed and optimized, and sequential modules will be combined in a single continuous-flow nanofactory. The multidisciplinary project will integrate contributions from high school students through graduate researchers, and result in development of a new nanomedicines designed for the treatment of recurrent pediatric neuroblastoma, a high-risk cancer with dismal clinical outcomes.Current techniques for liposomal drug synthesis must be re-engineered at each production scale, introducing manufacturing costs and engineering challenges that present significant barriers to the development of new liposomal drugs. Overcoming this gap is fundamentally a nanomanufacturing challenge. We will develop a multistage microfluidic flow focusing technology as a highly scalable method supporting the full production of liposomal nanomedicines in a continuous-flow process. The studies will yield new insights into the underlying multiscale physics for each processing stage, resulting in improved understanding of the chemophysical processes involved in liposome self-assembly, drug loading, and targeting agent attachment within the microfluidic system. The work will also result in new solutions to the key engineering challenges associated with coupling diverse continuous-flow microfluidic modules for advanced functionalized nanoparticle manufacturing. Performance of the technology will be evaluated using a novel nanomedicine test-bed. Specifically, the award will demonstrate a targeted polypharmaceutical comprising of an amphipathic chemotherapeutic (doxorubicin) together with a lipophilic tyrosine kinase inhibitor (erlotinib) for the treatment of pediatric neuroblastoma. Using this test-bed, a combination of scale-up and scale-out will be explored to provide a unified framework for multi-scale liposomal drug synthesis, vastly increasing the speed and reducing the complexity of nanomedicine manufacturing.