Design of siRNA Therapeutics from the Molecular Scale

Abstract

While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics.

Dextran functionalization enhances nanoparticle-mediated siRNA delivery and silencing

“…Moreover, if designed correctly, delivery vehicles can maximize delivery of the siRNAs to the target cells/tissues of interest 12 . Currently, lipoplexes (complexes of siRNA with lipids) and polyplexes (complexes of siRNAs with polymers) are the most prevalent among ongoing clinical trials with some in vivo successes 3,2,13–17 .…”

Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (B). Efficiency of pharmacological action

“…Silencing of target genes requires that siRNA is delivered into the cell in its intact (active) state. To achieve this, an effective vector protecting siRNA that is non-toxic and can be targeted at selected cells is necessary (Ambesajir et al, 2012;Angart et al, 2013). Novel non-viral vectors for siRNA, currently being developed and improved, include liposomes (Dorasamy et al, 2012), micelles (Kapoor et al, 2012), nanogels (Pereira et al, 2013), nanosuspensions (Endres et al, 2012), mesoporous silica (Lin et al, 2013) and quantum dots .…”

Dendrimers as Drug Nanocarriers: The Future of Gene Therapy and Targeted Therapies in Cancer

“…To design the most effective and variety therapies for different kinds of cancer, an effective vector protecting siRNA that is non-toxic and can be targeted at selected cells is necessary [91,92]. Several classes of dendrimers seem to be good candidates for carriers of oligonucleotides.…”