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Title page for ETD etd-12022013-175726

Type of Document Master's Thesis
Author Miteva, Martina
Author's Email Address martina.miteva@vanderbilt.edu
URN etd-12022013-175726
Title Optimizing PEG Molecular Weight and Molar Composition for Enhanced In Vivo Pharmacokinetics of a Mixed Micellar siRNA Carrier
Degree Master of Science
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Craig L. Duvall Committee Co-Chair
Todd D. Giorgio Committee Co-Chair
  • PEG
  • pharmacokinetics
  • siRNA
  • cationic micelles
  • in vivo
Date of Defense 2013-12-14
Availability unrestricted
RNA interference (RNAi) by small interfering RNA (siRNA) possesses great promise as a therapeutic for pathologies whose etiology is related to gene overexpression. However, due to the poor pharmacokinetic properties of siRNA, it requires a carrier for in vivo intravenous delivery. Historically, nucleic acid delivery systems have utilized cationic lipids or polymers as carriers, but such agents are poorly translatable in vivo, as they have inadequate hemo-stability, a short blood circulation half-life, and can lead to unexpected toxicity. Here, we introduce a series of novel mixed micelles that modulate the molar concentration and lengths of poly(ethylene glycol) (PEG) on the corona of the micelles to achieve charge shielding that improves the pharmacokinetic properties of the siRNA-micelle complex, while maintain significant levels of gene knockdown. Hemocompatibility and in vitro stability is increased for micelles with greater PEG surface concentration and for micelles with higher molecular weight PEG in the corona. When delivered intravenously in vivo, micelles with a higher molecular weight PEG in the corona demonstrate a significantly improved blood circulation half-life (17.8 minutes for micelles with a 20 kDa PEG vs. 4.6 minutes for micelles with a 5 kDa PEG) and a 4-fold decrease in lung accumulation. These improved in vivo pharmacokinetics have the potential to be applied to leverage the enhanced permeation and retention (EPR) effect for biodistribution to and gene silencing in vascularized tumors.
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