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

这项早期教师职业发展(Career)计划奖提供资金，以实现对竞争动力学的全面了解，所需的竞争动力学需要重复地产生封装具有最佳物理化学性质的疏水药物的聚合物纳米颗粒。聚合物纳米粒子作为药物载体具有较大的比表面积和生物利用度，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物纳米颗粒的主要挑战是在保持纳米颗粒性能一致的同时实现更大规模的生产。由于过程的复杂性，单纯的经验优化是不可行的，通过合理的模拟和实验的相互作用进行定量预测是必不可少的。利用时间分辨小角X射线散射与微流控装置相结合的方法，对纳米颗粒的结构演化进行了原位实验观测。计算流体动力学模型将与人口平衡方程一起发展，以数值理解混合与降水的耦合。模拟和实验之间的迭代将导致对纳米颗粒系统如何形成的基本理解，从而使有效地设计、优化和扩大纳米颗粒生产成为可能。如果成功，将开发出一种可扩展的纳米颗粒生产方法，这将导致各种纳米载体系统的快速临床转化，以输送疏水药物和检测和治疗复杂的疾病。实验和数值计算方法可作为优化分散多相反应条件的平台。以亚秒级分辨率对纳米粒子结构演化进行最先进的实验观测，将极大地加深我们对沉淀动力学和纳米粒子生产的理解。这项研究将被纳入国际和平研究所开发的课程，以及在跨学科环境中针对研究生、本科生和6-12岁学生的各种教育活动。实验和理论结果的高度可视化以及生物医学应用的社会相关性是招收科学、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.