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Title page for ETD etd-03202015-092139


Type of Document Master's Thesis
Author Werfel, Thomas Anthony
Author's Email Address thomas.a.werfel@vanderbilt.edu
URN etd-03202015-092139
Title Combinatorial Library of Ternary Polyplexes Enables Identification of Improved siRNA Nanocarriers for Rapid In Vivo Translation
Degree Master of Science
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Craig L Duvall Committee Chair
Todd D Giorgio Committee Member
Keywords
  • Polyplexes
  • pH-responsive
  • intravenous delivery
  • siRNA
Date of Defense 2015-04-08
Availability unrestricted
Abstract
A combinatorial library of ternary polyplexes was herein investigated to optimize formulations for siRNA delivery. The compositions tested build from our previous finding that balancing cationic and hydrophobic content in binary polyplexes can enhance both particle stability and endosome escape. Through this ternary complex/combinatorial approach, we were able to systematically study important structure-function characteristics such as polyplex surface PEGylation density, size, stability, and endosomolysis. Ternary polyplexes which were optimized to overcome multiple barriers to siRNA delivery achieved highest gene silencing and endosomolysis was identified as a crucial parameter for achieving siRNA silencing in vitro. Lead ternary polyplexes identified from multiparametric screens, DB-50B412, were able to localize to tumors after intravenous administration and achieved enhanced target gene silencing of the model gene luciferase in vivo.
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