Elucidation of Design Criteria for Non-Viral Gene Delivery Vector Development
Gabrielson, Nathan
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https://hdl.handle.net/2142/87868
Description
Title
Elucidation of Design Criteria for Non-Viral Gene Delivery Vector Development
Author(s)
Gabrielson, Nathan
Issue Date
2009
Doctoral Committee Chair(s)
Pack, Daniel W.
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Engineering, Chemical
Language
eng
Abstract
Cellular association, endocytosis, vector escape from the endosomal pathway, dissociation of DNA from its non-viral carrier, migration of DNA to the nucleus, nuclear entry and finally transcription all stand as obstacles to gene delivery. The research presented in this thesis addresses the issue of gene delivery efficiency by studying vector dissociation and endocytosis. Chapter 2 examines dissociation by reducing the electrostatic interaction between DNA and the polymeric gene delivery agent polyethylenimine (PEI). The results indicate that weakened polymer/DNA interactions increase gene delivery efficiency and, more generally, that the strength of polymer/DNA interactions needs to be considered and optimized when designing non-viral vectors. In application of this optimization principle, Chapter 4 describes the use of crosslinked vectors that break down inside the cell into weak-binding low molecular weight monomer units. Chapter 3 explores endocytosis and the impact of targeting vectors to two distinct endocytic routes---the caveolar and clathrin pathways. The data suggests that successful PEI-mediated gene delivery proceeds exclusively via the caveolar pathway in HeLa cells and that when targeting vectors to specific cells and tissues, the ligand and its resulting endocytic route need to be considered. Finally, Chapter 5 demonstrates how the principles of optimizing DNA/polymer interactions and even ligand attachment can be applied to dendron-based gene delivery vectors.
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