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Title page for ETD etd-03272017-155710

Type of Document Dissertation
Author Sarett, Samantha Mara
Author's Email Address samantha.sarett@vanderbilt.edu
URN etd-03272017-155710
Title Hydrophobic Modification of siRNA to Improve Delivery and Efficacy of RNAi Therapeutics
Degree PhD
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Craig Duvall Committee Chair
Dana Brantley-Sieders Committee Member
Jeffrey Davidson Committee Member
Scott Guelcher Committee Member
Todd Giorgio Committee Member
  • hydrophobic modification
  • delivery efficacy
  • pharmacokinetics
  • gene silencing
  • siRNA
Date of Defense 2017-03-16
Availability unrestricted
Small interfering RNA (siRNA) can potently and specifically suppress translation of any gene, including intracellular targets traditionally considered “undruggable”. 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.
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