The research objective of this award is to explore systematic methods to scale-up the high-rate production of a novel and robust lipid-coated polymeric drug delivery nanoparticle and to understand the principles underlying the large-scale nanoparticle fabrication process. The approach taken will be to develop and utilize a stirred-tank reactor and a multi-inlet vortex reactor to pursue the target large-scale and high-rate production of the drug delivery nanoparticles. Both the batch mixing theory and the continuous mixing theory will be studied for understanding and optimizing the nanoparticle fabrication process. All synthesized nanoparticles will be systematically characterized regarding particle size, surface charge and morphology, drug loading yield, drug release kinetics, and stability in serum by a series of analytical tools to evaluate their reproducibility and scalability.
If successful, the benefits of this research will include both increased scientific understanding and technological developments on both nanoparticle drug delivery and nanomanufacturing. This research can push forward the frontier of current nanomedicine research by providing therapeutically relevant quantities of drug-loaded nanoparticles for possible clinical use. The experimental and theoretical findings from this study can be generalized for high-throughput production of other nanoscaled agents and can contribute to the general understandings of nanomanufacturing. Moreover, this project will highly integrate research and education activities. The educational efforts include recruitment of underrepresented undergraduate students working in the laboratory on the project, recruitment of high school students, with an emphasis on minority summer interns to perform 4~8 weeks of research, and development of new courses on nanomedicine and nanofabrication for both undergraduate and graduate students to further disseminate the findings from the research.
Poor manufacturing scalability has become a key issue that impedes the development and translation of many nanoparticle-based drug delivery platforms. In this project, the PI carried out a research program to explore systematic approaches to scale-up of a novel and robust lipid-coated polymeric drug delivery nanoparticle for high-rate production and to understand the principles underlying the large-scale nanoparticle fabrication process. The primary goal of this project is to improve the production rate of these biocompatible nanoparticles from the current 1~5 mg/hr to 10000~50000 mg/hr. This 10000-fold increase of production rate would allow producing enough drug-loaded nanoparticles for preclinical and clinical tests of the therapeutic nanoparticles. More importantly, the nanoparticle manufacturing techniques and the corresponding fundamental understandings developed through this project can be generalized for high-throughput production of other nanoscale particles for broader applications. Supported by this award, a sonication-based batch reactor and a multi-inlet vortex reactor (MIVR) have been developed and utilized to pursue the target production rate, based on the batch mixing theory and the continuous mixing theory, respectively. All produced nanoparticles have been systematically characterized by a series of analytical tools to evaluate their physicochemical properties, reproducibility and scalability. These results have led to 15 peer-reviewed articles. The working mechanism of the sonication method is illustrated in Figure 1. This method can be used to synthesize high quality lipid-polymer hybrid nanoparticles within a wide range of relative concentrations of polymers, lipids, and lipid-polyethylene glycol conjugates. The resulting nanoparticles had sub-100 nm particle size and less than 0.10 polydispersity index. These particles were proven to have long-term stability in PBS buffer solution and did not aggregate when suspended in fetal bovine serum, indicating great promise to be used in vivo. As this new method does not involve the use of sample heating, vortexing, or solvent evaporation, it reduces the time needed to prepare the same amount of hybrid nanoparticles by a factor of about 20 without compromising the quality of particles. This approach makes it possible to scale up the production of lipid-polymer hybrid nanoparticles for possible preclinical and clinical tests in the future. The working mechanism of the MIVR device is illustrated in Figure 2. This device can be utilized to produce lipid-polymer hybrid nanoparticles with a production yield up to 10 g/hr, nearly 10,000-flod more effective than the current lab-scale synthesis rate. Using the MIVR device, it was demonstrated that several different variables, including formulation, polymer concentration, and flow rate through the device had marked effects on the final particle characteristics. Hybrid nanoparticles synthesized using the MIVR were comparable to lab-scale particles in both their physicochemical properties and stability in PBS and serum. When scaling up the formulation, there is a tradeoff between production yield and the desired particle characteristics. This needs to be considered when tailoring the large-scale production to meet the requirements of specific applications. Use of the MIVR appears to be a viable strategy for producing hybrid nanoparticles in clinically significant quantities. This award also significantly enhanced scientific education among K-12 students. During the award period, a total of 5 highly motivated high school students have been accepted to directly work on the project. The research program also hosted visits from high school teachers and their classes to learn more about nanotechnology and nanomanufacturing. It’s expected that this laboratory experience would build a bridge between how sciences are taught in high school and what is expected in universities. In addition, this project provided undergraduate students with stimulating research experience. A total of 10 undergraduate students have been involved in this project during the entire award period. These hands-on laboratory training is extremely helpful for undergraduates to decide their future career path. Moreover, the research findings from this project have been effectively disseminated to the public in large through a series of educational lectures including 35 invited talks and 21 contributed presentations at various national and international conferences and institutional seminars. The audiences included professionals, graduate students, undergraduate students, high school students and teachers, and general public. Collectively, these activities have generated tremendous broader impacts of this project.
