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Development, Optimization and Validation of a Chitosan-Zein Dual-Material Non Viral Gene Delivery System for Applications in Oral Gene Delivery
The development of non viral gene delivery platforms can impact a wide range of applications to improve human health, including gene and cell therapies, tissue engineering, and DNA vaccination. To better facilitate efficient expression of therapeutic transgenes, non viral gene delivery systems that take advantage of alternative administration routes to facilitate patient compliance, simple and repeated dosing, and allow for local and systemic transgene production, are needed. The oral route is an ideal delivery route for gene-based therapeutics due to the large cellular surface area and highly vascularized nature of the intestinal epithelium, which presents large populations of cells, including immune cells, for transgene production to generate local (i.e. mucosal) and systemic responses. While the oral route has clear advantages for gene delivery applications, it also poses unique challenges to achieving successful non viral gene delivery, including harsh and variable environments (i.e. stomach and intestine). Therefore, there remains a need for novel biomaterial-based non viral gene delivery platforms that adequately protect orally delivered nucleic acids and allow for efficient production of transgene. In this dissertation, a novel dual-material oral gene delivery platform consisting of zein and chitosan was developed to improve oral non viral gene delivery. Chitosan (CS), a polymer widely used for non viral gene delivery, was used to form complexes with DNA for efficient transfection; these complexes are then encapsulated in zein, a natural corn protein that is resistant to acidic environments and degradation by gastric enzymes, to improve protection of CS/DNA complexes in gastric conditions and effectively deliver complexes in the intestine. This dual-material system, termed Chitosan-Zein-Nano-in-Microparticles (CS-ZN-NIMs) was characterized for parameters critical to successful oral gene delivery and investigated as a platform for oral DNA vaccination. Moreover, the base CS-ZN-NIM platform was modified to improve targeting and transfection of immune cells, and evaluated for the induction of immune responses following oral delivery. The work presented in this dissertation describes the first reported use of both zein and chitosan for applications in oral non viral gene delivery, and provides insights into critical particle features that can be tuned to improve oral delivery for applications in DNA vaccination.
Farris, Eric, "Development, Optimization and Validation of a Chitosan-Zein Dual-Material Non Viral Gene Delivery System for Applications in Oral Gene Delivery" (2019). ETD collection for University of Nebraska - Lincoln. AAI13814414.