Preparation of Nanoparticles from Microemulsions Using Supercritical Antisolvent Precipitation

CBET-0827806 ZareIntellectual Merit：需要制备具有可控形状、尺寸分布甚至控制其周围物质的生物活性纳米颗粒。此外，为了实用，这样的过程必须按比例放大到大的数量（在千克的水平上，这排除了逐个原子的方法）并且是环境友好的（绿色化学）。我们建议使用一种新技术来完成这一任务，其中两种不混溶的液体（如油和水）的微乳液作为微小的液滴喷射到第三相（超临界二氧化碳）中，该第三相溶解一相而不是另一相，导致不溶相沉淀。实际上，情况可能更复杂，其中感兴趣的生物活性化合物是不溶的，而其他两相溶解在超临界CO2中。通过添加合适的生物相容性聚合物，我们可以封装我们的纳米颗粒，用于延时释放或靶向特定细胞吸收。使用超临界二氧化碳作为从微乳液中沉淀所需生物活性化合物的抗溶剂是一个需要深入基础研究的主题，然后才能实现其可能的优点。我们已经获得了初步的数据，这些数据鼓励我们相信这种方法可以发展成为一种新的药物输送方法。 这项研究计划将与瑞典哥德堡的查尔默斯科技大学的Krister Holmberg教授合作完成。他的团队拥有在微乳液中形成无机纳米颗粒的专业知识，可以在受控的反应条件下形成5-10 nm的颗粒。我们为这次合作带来了在超临界流体中形成和控制纳米颗粒的专业知识。一个重要的新方面将是增加封装过程以及颗粒的物理评价。这项工作的范围将从纳米颗粒如何形成的基础研究，到它们在生物系统中的行为，通过研究它们在药物控制释放实验中的应用和在活体动物中的分布。这两个小组的努力相互补充，增加了该项目成功的可能性。更广泛的影响：该项目的目标是开发一种新的工艺，允许纳米颗粒的形成和广泛选择的目标化合物的封装。该方法将产生具有窄尺寸分布的1-5 nm范围内的颗粒，并且允许以高产率进行原位包封。该过程将需要低温（35-45 ℃）以及最少的加工步骤，使其与生物活性化合物相容，并足够快速用于标记研究。所提出的工艺的其他优点是减少有毒废物和直接放大工艺参数，以实现大批量生产的潜力。显然，这种方法的成功将对制药、微电子、食品、油漆和化妆品等其他领域产生深远的影响。此外，本研究项目将在化学，生物学和工程学的交叉领域提供一名研究生的培训

CBET-0827806ZareIntellectual Merit: The need exists to prepare biologically active nanoparticles with controlled shape, size distribution, and even to control what surrounds them. Moreover, to be practical, such a procedure must scale to large quantities (on the kilogram level which precludes atom-byatom approaches) and be environmentally friendly (green chemistry). We propose to accomplish this task using a new technique in which a microemulsion of two immiscible liquids (such as oil and water) is sprayed as tiny droplets into a third phase (supercritical carbon dioxide) that dissolves one phase and not the other, causing the insoluble phase to be precipitated. Actually, the situation may be yet more complex in which the biologically active compound of interest is what is insoluble whereas the other two phases dissolve in the supercritical CO2. By the addition of suitable biocompatible polymers, we can encapsulate our nanoparticles for time-delayed release or for targeting to specific cells for uptake. The use of supercritical carbon dioxide as an antisolvent for the precipitation of desired biologically active compounds from microemulsions is a subject requiring deep fundamental study before its possible advantages can be realized. We have already obtained preliminary data that encourages us to believe that this approach can be developed into a new drug delivery methodology. The research proposal is for work to be done in collaboration with Professor Krister Holmberg at Chalmers University of Technology, Gothenburg, Sweden. His group has expertise in formation of inorganic nanoparticles in microemulsions allowing 5-10 nm particles to be formed at controlled reaction conditions. We bring to this collaboration the expertise in the formation and control of nanoparticles in supercritical fluids. An important new aspect will be the added encapsulation process as well as physical evaluation of the particles. The work will range from fundamental studies of how nanoparticles are formed to how they behave in biological systems by studying their use in drug-controlled release experiments and distribution in living animals. The efforts of these two groups complement one another in a way that increases the likelihood for success of this project.Broader Impact: The goal of the project is to develop a new process which allows for nanoparticle formation and encapsulation of a wide selection of target compounds. The process will yield particles in the 1-5 nm range with a narrow size distribution as well as allow for insitu encapsulation with high yield. The process will require low temperatures (35-45 C) as well as minimal processing steps, making it compatible with bioactive compounds and rapid enough for labeling studies. Other advantages of the proposed process are reduction in toxic waste and direct scale up of the process parameters to realize the potential of achieving high-volume manufacturing. Clearly, the success of such a procedure will have profound impacts on other fields that span pharmaceuticals, microelectronics, foodstuffs, paints, and cosmetics. In addition, this research project will provide training of one graduate student in a truly interdisciplinary area at the cross section of chemistry, biology, and engineering