Small interfering RNA (siRNA) can potently and specifically suppress translation of any gene, including intracellular targets traditionally considered âundruggableâ. However, emergence of translational siRNA therapies has remained slow, with the primary challenge being the formidable anatomical and physiological barriers that must be overcome to deliver siRNA to its intracellular site of action in target cell types. Polymeric nanoparticle (NP) carriers can protect the siRNA against degradation and transport it into the cell, but these polyelectrolyte systems are hampered by poor in vivo stability and toxic/immunogenic effects. Hydrophobic modification of siRNA is a promising approach to improve the pharmacokinetic properties of siRNA without the complexity and toxicity of traditional NP carriers. siRNA conjugated to the lipid palmitic acid (PA) acts synergistically with two distinct polymer NP carriers, improving carrier stability, pharmacokinetics, and cellular internalization, leading to enhanced gene silencing efficacy at reduced polymer doses. Modification of siRNA with PA is thus a powerful strategy to broaden the therapeutic index of NP-based strategies. Additionally, conjugation of an albumin-binding hydrophobe (termed L2) to siRNA broadly enhances its pharmacokinetic profile, biodistribution to tumors, and tissue penetration capacity. siRNA-L2 consistently outperformed a commercial NP carrier in tumor accumulation and biocompatibility and elicited significant and sustained in vivo tumor gene silencing, highlighting its potential as a translational and potentially transformative approach to improve systemic RNAi cancer therapies. The benefits conferred through PA and L2 conjugation establish a pivotal role for hydrophobic siRNA conjugates in the advance of siRNA to medical application.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03272017-155710 |
| Date | 27 March 2017 |
| Creators | Sarett, Samantha Mara |
| Contributors | Dana Brantley-Sieders, Scott Guelcher, Jeffrey Davidson, Todd Giorgio, Craig Duvall |
| 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-03272017-155710/ |
| Rights | restrictsix, 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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