siRNA-induced RNAi responses have great potential to selectively treat human disease, especially cancer with its myriad of genetic mutations.  However, due to their 14 kDa size and 40 negative anionic charges, siRNAs have no bioavailability to enter cells and require a delivery technology.  We have focused our delivery efforts on synthesizing short interfering RiboNucleic Neutral (siRNN) prodrug molecules that contain bioreversible, phosphotriester groups that are specifically cleaved by cytoplasmic thioesterases to convert the siRNN prodrug into intracellularly active siRNA that induces robust RNAi responses.  We have developed and optimized phosphotriester phosphoramidite synthesis pathways, deprotection and purification conditions that result in high yielding siRNN oligonucleotides.  siRNNs have favorable drug-like properties, including high stability in human serum, absence of innate immune stimulation and solubility.  Targeted delivery of siRNN prodrugs results in robust RNAi responses in vivo.  siRNN prodrugs represent a novel approach to induce RNAi responses by delivering one molecule at a time into cells with the smallest possible size of <20 kDa.

Induction of RNAi responses by self-delivery of bioreversible phosphotriester siRNN prodrugs

248th National Meeting (2014)

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