Trafficking and efficacy of cationic polymers as DNA vaccine carriers and anti-cancer agents

University of Minnesota Ph.D. dissertation. June 2013. Major: Biomedical Engineering. Advisor: Chun Wang, PhD. 1 computer file (PDF); ix, 135 pages.The potential of DNA vaccines for treatment of diseases such as HIV and cancer are overwhelming, due to the fact that DNA vaccines can activate both a cell-mediated (T-cell) and humoral (antibody) immune response. However, the most commonly occurring problem of DNA vaccines is limited transgene delivery and expression. Currently, much effort has focused on designing an optimal polymer system that is stable, can protect and deliver DNA, as well as offer high transgene expression. Unfortunately, the ability of polymer based systems to produce robust gene expression, have yet to show substantial improvement. The major obstacle hindering successful transgene expression can be attributed to the interactions of the polymer-DNA complex with the subcellular environment. Therefore, we focused on understanding the structure-functional relationship of a well-defined simple polymer based system and how they might lead to improved transgene expression. First, we investigated the effect of polymer molecular weight and backbone structure on transgene expression as it pertains to subcellular trafficking. Second, we focused on the relationship between polymer-DNA complexes and different dendritic cell-types as a function of maturation state. Lastly, we looked into how further modification of a cationic polymer can lead to elevated cytotoxicity and use as an anti-cancer agent. The results from this work can be used as a design template to improve the overall subcellular trafficking and efficacy of cationic polymer based DNA vaccines or anti-cancer agents