Grants and Contracts Details


Intellectual Merit: Human gene therapy holds tremendous promise for treatment of conditions from cystic fibrosis to cardiovascular disease to cancer, but clinical implementation has been hindered by the lack of safe and efficient methods for delivery of genetic material. Most gene therapy trials have employed recombinant viruses, which possess hierarchical structure and functions evolved for efficient gene delivery, but present serious safety concerns. Non-viral vectors, such as cationic polymers, can be designed to be biocompatible and non-immunogenic; allow celltype specificity via attachment of targeting ligands; and are more robust and amenable to formulation. However, non-viral vectors lack the delivery efficiency necessary for clinical use. Although the chemistry of polymeric gene delivery agents has been the focus of much research for more than two decades, the fabrication and resulting structure of polymer/DNA complexes (polyplexes) has received little attention. Conventional polyplex assembly methods, via simple mixing, allow limited control of polyplex size, size uniformity, or spatially defined arrangement of the DNA and polymer(s). Enhanced control of assembly—including the capability of producing multilayered polyplexes comprising two or more synthetic agents that each provide specific functionality—will be critical to the design of non-viral vectors with clinically relevant activity. We are developing microfluidic systems for construction of monodisperse, multilayered, multifunctional non-viral vectors. The devices bring solutions of plasmid DNA and polycations into contact under laminar flow providing control of polymer/DNA stoichiometry and interaction times and allowing introduction of multiple materials in a sequential fashion and defined spatial arrangement. The goals of the project are: (1) to construct a microfluidic polyplex assembly device and demonstrate control of polyplex size and uniformity; (2) to design a secondgeneration device for layer-by-layer (LbL) assembly of multifunctional polyplexes comprising plasmid DNA and polymers of alternating charge; and (3) to demonstrate the efficiency of monodisperse and LbL polyplexes for gene delivery to human cell lines. Broader Impacts: The proposed research could ultimately impact basic biological research requiring efficient gene delivery to cells in culture as well as development of human gene therapy. Perhaps more importantly, however, this project represents a first attempt (to our knowledge) to develop methods for reproducible, robust manufacture of multi-layered, multifunctional synthetic gene delivery agents. The aims of the project, therefore, are designed not to merely generate an effective vector, but to develop new understanding of vector assembly, how it can be controlled, and its impact on vector performance. The main impact of this project may be methods and devices that can be readily adopted by researchers around the globe. The proposed project will also impact education for pre-college, undergraduate, and graduate students. This interdisciplinary project is expected to provide excellent training for graduate and undergraduate students in the PI’s lab. Students at all levels will be recruited to this project from engineering, pharmaceutical sciences, and basic science disciplines. In addition, the PI and undergraduate students will develop a module for outreach to high school girls through UK’s Girls in Engineering, Mathematics and Science program that will introduce students to chemical engineering principles of fluid dynamics.
Effective start/end date7/15/146/30/18


  • National Science Foundation: $300,000.00


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