Non-viral gene delivery continues to suffer from the lack of safe and efficient polymeric carriers because the underlying mechanism of polymer mediated gene transfer and expression is still not fully understood. Current undefined and polydisperse synthetic polymer systems are not good models for investigating structure-function relationship of polymeric gene carriers. Furthermore, in the context of DNA vaccine delivery, there is a lack of understanding of the interaction between polymer/DNA complexes (polyplexes) and antigen presenting cells (APCs). In this work, we aimed to reveal the structure-function relationship of polymers for DNA vaccine delivery by employing polymers with well-defined chemical structure and narrow molecular weight distribution synthesized by living radical polymerization. We also explored the cytotoxicity of certain cationic amphiphilic polymers for anticancer application. First, we focused on understanding the effect of polymer molecular weight of poly(2-aminoethyl methacrylate) (PAEM) on DNA vaccine delivery. Second, the relationship between hydrophobicity of polymers and their performance in gene delivery to dendritic cells was investigated by using well-defined cationic poly(aminoalkyl methacrylate) (PAAM) polymers with varied length of side groups. Lastly, we evaluated the possibility to use a synthetic membrane lytic poly(6-amino-1-hexyl methacrylate) (PAHM) polymer which kills cancer cells effectively as an anticancer agent. We also described a strategy to reversibly mask the cytotoxicity of PAHM by forming acid sensitive PAHM-maleate conjugates for future in vivo applications.
University of Minnesota Ph.D. dissertation. November 2013. Major: Biomedical Engineering. Advisor: Chun Wang. 1 computer file (PDF); xi, 111 pages, appendices I-II.
Synthetic polymers with well-defined structures for DNA vaccine delivery and cancer therapy.
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