Small molecule modification of short oligonucleotides to improve gene silencing therapy

Small interfering RNA (siRNA) is becoming a prevalent oligonucleotide-based therapy because of its ability to silence genes that contribute to debilitating diseases. One known method of improving the delivery of oligonucleotides is through the direct conjugation of a small, targeting molecule. This thesis develops methods to attach three previously unexplored classes of molecules (an antiestrogen, a ceramide, and a bioreducible fluorophore) that overcome several barriers to siRNA delivery. Overall, these materials represent an example of the possibilities for the direct chemical conjugation of commercially-available oligonucleotides and provide a platform for the easy introduction of other modifications of interest.