Intellectual 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
