Since its discovery by Fire and Mello, RNA interference (RNAi) has been established as a potential route for gene-silencing therapy and anticipated as a possible remedy for various diseases such as cancer, viral diseases, diabetes, and gene disorders. However, the development of RNAi therapies has been significantly impeded due to the difficulties in delivery of the nucleic acid into the cells. Recently, lipoplexes and stable nucleic acid lipid particles (SNALPs) have shown to be effective at encapsulating small-interfering RNA (siRNA) for gene-silencing therapy. In particular, the presence of tertiary amines and unsaturated hydrocarbon chains in the lipid portion appear to assist in siRNA interaction and delivery. Our lab envisioned the use of guanidylated amphiphiles and bolaamphiphiles (long hydrophobic chains with polar heads at each end) in the formation of lipoplexes with RNA for delivery applications. The use of guanidine in place of amines should increase the amount of H-bonding interactions to provide more stable complexes. Here, we report the progress towards the synthesis and characterization of a guanidylated amphiphile synthesized from oleyl alcohol and a guanidylated bolaamphiphile from 10-undecenoic acid using a Grubbs' catalyst for olefin metathesis. Additionally, we have synthesized a saturated bolaamphiphile to investigate the observation that unsaturated lipids aid in the delivery of siRNA. These lipids will be combined with RNA to form nanoparticles, which will be characterized for size and dispersity using dynamic light scattering (DLS). Future work will include biological studies to assess the ability of these lipids as siRNA delivery modalities. This work was partially supported by NIGMS MARC U*STAR GM007717, NIGMS MBRS-RISE GM60655, and the Department of Chemistry at the University of Texas at San Antonio.

Synthesis of guanidylated amphiphiles and bolaamphiphiles for siRNA encapsulation in gene-silencing therapy

247th National Meeting (2014)

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