CAREER: Understanding Nanoprecipitation - Scalable Production of Polymeric Nanoparticles Encapsulating Hydrophobic Compounds

这个早期教师职业发展（Career）计划奖提供资金，以实现对竞争性动力学的全面理解，以可重复地产生具有优化物理化学性质的包覆疏水药物的聚合纳米颗粒。高分子纳米颗粒作为药物载体，由于其具有较大的表面体积比，可以显著提高疏水化合物的溶解度和生物利用度。开发用于临床应用的聚合纳米颗粒的主要挑战是在保持纳米颗粒特性一致的情况下进行大规模生产。由于过程的复杂性，纯粹的经验优化是不可行的，通过模拟和实验的明智相互作用进行定量预测是必不可少的。采用时间分辨小角x射线散射与微流控装置相结合的方法，原位实验观察纳米颗粒的结构演变。将发展计算流体动力学建模和种群平衡方程，以数值理解混合与降水的耦合。建模和实验之间的迭代将导致对纳米粒子系统如何形成的基本理解，从而使有效设计、优化和扩大纳米粒子生产成为可能。如果成功，一种可扩展的纳米颗粒生产方法将被开发出来，这将导致各种纳米载体系统的快速临床转化，以输送疏水药物并检测和治疗复杂疾病。实验和数值方法可以作为优化分散多相反应条件的平台。亚秒分辨率纳米粒子结构演化的实验观测将大大提高我们对沉淀动力学和纳米粒子产生的理解。该研究将被整合到PI开发的课程中，以及针对研究生、本科生和6-12岁学生的跨学科教育活动中。实验和理论结果的高度视觉性以及生物医学应用的社会相关性代表了招募科学，技术，工程和数学（STEM）学科学生的自然吸引力。

This Early Faculty Career Development (CAREER) Program award provides funding to achieve a comprehensive understanding of the competitive kinetics required to reproducibly generate polymeric nanoparticles encapsulating hydrophobic drugs with optimized physicochemical properties. Polymeric nanoparticles as drug carriers can dramatically increase the solubility and bioavailability of hydrophobic compounds due to their large surface to volume ratio. The major challenge of developing polymeric nanoparticles for clinical applications is the production at larger scale while maintaining consistent nanoparticle properties. Due to the complexity of the process, purely empirical optimization is infeasible and quantitative prediction by a judicious interplay of simulations and experiments is essential. Time-resolved small-angle X-ray scattering integrated with a microfluidic device will be employed to experimentally observe nanoparticle structural evolution in situ. Computational fluid dynamics modeling together with population balance equations will be developed to numerically understand the coupling of mixing with precipitation. Iteration between modeling and experiments will lead to a fundamental understanding of how nanoparticle systems form, thus making it possible to efficiently design, optimize, and scale up nanoparticle production. If successful, a scalable method of nanoparticle production will have been developed, which will lead to rapid clinical translation of a variety of nanocarrier systems to deliver hydrophobic drugs and to detect and treat complex diseases. The experimental and numerical methods can be used as a platform to optimize conditions for dispersed multi-phase reactions in general. The state-of-the-art experimental observation of nanoparticle structural evolution with sub-second time resolution will greatly enhance our understanding of precipitation kinetics and nanoparticle production. The study will be integrated into the courses developed by the PI as well as into various educational activities targeting graduate, undergraduate, and 6-12 students in an interdisciplinary setting. The highly visual nature of the experimental and theoretical results and the societal relevance of the biomedical applications represent a natural draw for recruiting students to Science, Technology, Engineering, and Math (STEM) disciplines.