Continuous-Flow Microfluidic Nanomanufacturing of Nanomedicines

University Of Maryland, College Park, College Park MD

Investigators

Abstract

Nanoparticle-enabled drugs hold enormous potential for improving human health, allowing drug designers to tailor the delivery of therapeutic compounds to specific tissues or cells, and optimize the uptake of drugs into those cells. In particular, the use of lipid vesicles or liposomes as nanoscale drug carriers has resulted in significant advances toward the treatment of a range of cancers. However, the transition of liposomal nanomedicines from the lab to the clinic remains constrained by the lack of nanomanufacturing methods capable of scaling across the full production range. This award will investigate continuous-flow microfluidics technology as a unique scalable approach to bridge this gap. This technology will leverage chemical and physical phenomena across multiple size scales within a continuous-flow microfluidic system, resulting in nanoparticle self-assembly, passive and active drug loading, nanoparticle functionalization, and drug purification and concentration. Individual fluidic modules will be developed and optimized, and sequential modules will be combined in a single continuous-flow nanofactory. The multidisciplinary project will integrate contributions from high school students through graduate researchers, and result in development of a new nanomedicines designed for the treatment of recurrent pediatric neuroblastoma, a high-risk cancer with dismal clinical outcomes. Current techniques for liposomal drug synthesis must be re-engineered at each production scale, introducing manufacturing costs and engineering challenges that present significant barriers to the development of new liposomal drugs. Overcoming this gap is fundamentally a nanomanufacturing challenge. We will develop a multistage microfluidic flow focusing technology as a highly scalable method supporting the full production of liposomal nanomedicines in a continuous-flow process. The studies will yield new insights into the underlying multiscale physics for each processing stage, resulting in improved understanding of the chemophysical processes involved in liposome self-assembly, drug loading, and targeting agent attachment within the microfluidic system. The work will also result in new solutions to the key engineering challenges associated with coupling diverse continuous-flow microfluidic modules for advanced functionalized nanoparticle manufacturing. Performance of the technology will be evaluated using a novel nanomedicine test-bed. Specifically, the award will demonstrate a targeted polypharmaceutical comprising of an amphipathic chemotherapeutic (doxorubicin) together with a lipophilic tyrosine kinase inhibitor (erlotinib) for the treatment of pediatric neuroblastoma. Using this test-bed, a combination of scale-up and scale-out will be explored to provide a unified framework for multi-scale liposomal drug synthesis, vastly increasing the speed and reducing the complexity of nanomedicine manufacturing.