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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12022013-175726 |
| Date | 12 December 2013 |
| Creators | Miteva, Martina |
| Contributors | Craig L. Duvall, Todd D. Giorgio |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12022013-175726/ |
| Rights | restrictone, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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