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The design, synthesis, and evaluation of molecular transporters for the delivery of siRNA, and the application of molecular transporters to new cell types and new release strategies [electronic resource] / Erika Isabella Geihe Stanzl.

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Author/Creator:
Stanzl, Erika Isabella Geihe.
Language:
English.
Publication date:
2013
Imprint:
2013.
Format:
  • Book, Thesis
  • 1 online resource.
Note:
Submitted to the Department of Chemistry.
Note:
Thesis (Ph.D.)--Stanford University, 2013.
Summary:
My graduate studies have focused on the development of novel drug delivery technologies of research, clinical, and industrial significance. More specifically, my research has focused on the design, synthesis, and application of guanidinium-rich molecular transporters for the delivery of siRNA into cells. My studies have also focused on using molecular transporters to develop the first molecular method to deliver cargo into algae, and on the development of new strategies to control the timing and amount of drug or probe release in cells. Though all of this research is fundamentally based on organic chemistry, these projects have broad applications in research, industrial and clinical settings. Chapter 1 reviews the strategies that have been developed for the delivery of siRNA in both cells and animals. Rather than divide the field by chemical type (e.g. peptide vs. protein) or disease indication, this review categorizes siRNA deliver agents by the identity of their cationic moiety for siRNA complexation. Guanidinium-containing delivery vectors are presented, as are vectors containing ammonium and phosphonium groups. Highlighting this field by cationic moiety reveals how little research has been done to compare the effects of the cation's identity on deliver efficacy, toxicity, and pharmacokinetics. Chapter 2 describes the design, synthesis, and evaluation of guanidinium-rich amphipathic oligocarbonate molecular transporters for the complexation, delivery, and release of siRNA in cells. The synthetic ease of the metal-free carbonate oligomerization to synthesize these transporters afforded fast access to a series of transporters that systematically probed the functionality required for effective complexation, delivery, and release of siRNA. Transporters were characterized and evaluated for biological activity in immortalized human keratinocytes. The transporters discovered in this study were highly effective, with target gene silencing of up to 90% observed. Chapter 3 focuses on efforts towards expanding the scope of both the chemical space and cell types tested in the delivery of siRNA with amphipathic oligocarbonate molecular transporters. These second generation delivery systems have improved physical properties, including smaller and more stable particle sizes, relative to their first generation counterparts described in Chapter 2. These transporters delivered siRNA to primary keratinocytes, melanoma cells, and ovarian cancer cells. Chapter 4 details the development of the first molecular method for the delivery of small molecule probes and large protein cargos into algal cells. It was shown that oligoarginine could facilitate the uptake of fluorescein, or the larger, FAM-streptavidin protein, into cells. A catalytically active protein was delivered into cells and was shown to maintain catalytic activity even after delivery. Chapter 5 describes the design of new strategies to control the timing and amount of cargo released inside cells. Efforts towards a novel linker carrying two copies of drug or probe are described, as well as the combination of microneedles and luciferin-transporter conjugates for transdermal delivery in vivo.
Contributor:
Wender, Paul A., primary advisor.
Kanan, Matthew William, 1978- advisor.
Waymouth, Robert M., advisor.
Stanford University. Department of Chemistry.

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