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Aptamers for siRNA delivery

15th May 2019

siRNA’s are functional double stranded RNA molecules which can be used to control gene expression by targeting a messenger RNA and promoting its degradation.  One of the challenges in the therapeutic application of siRNA’s is targeting and delivery of the siRNA, to the cell / tissue of interest. Various adjuvants have been tested to increase the uptake of siRNA’s into cells however there is currently no gold standard.

In recent years numerous aptamers have been reported, which have specific cell targeting and penetrating properties. As both aptamers and siRNAs are composed of nucleic acid (and may be prepared by solid phase synthesis), it is relatively straightforward to combine aptamers with siRNA’s to make a chimeric molecule.

Early examples of this approach were reported by McNamara et al. (2006), in which PSMA binding aptamers were used to deliver the siRNA to prostate cancer cells and tumour vascular endothelium. The data shows that the aptamer successfully delivers the construct to the target cells. Once the siRNA has been internalised and processed, the siRNA target proteins are depleted, and cell death occurs. Importantly the aptamer portion of the chimera ensures that only cells which express PSMA are affected by the siRNA.

Liu et al. (2016) also used a PSMA binding aptamer to develop a bivalent aptamer-duel siRNA chimera called PSMA aptamer-Survivin siRNA-EGFR siRNA-PSMA aptamer (PSEP). By incorporating 2 different siRNAs into the PSEP, the construct is able to inhibit EGFR and Survivin simultaneously; which has been shown to induce apoptosis both in vitro and in vivo.

More recent efforts have focussed on development of chimeric molecules to enhance the specificity of therapeutic oligonucleotides. Jeong et al (2017) incorporated both siRNA and chemotherapeutic agents into one multivalent molecule. Interestingly they also incorporated reducible linkers between the aptamers and siRNA to facilitate siRNA release within the cell. By using two therapeutic modalities in a single delivery system, it was possible to induce an efficient anti-cancer action on drug-resistant cancer cells.

Each of these examples share one defining feature: a highly specific cell targeting aptamer which is internalised by the target cells or tissue. At Aptamer Group we have developed strategies to select aptamers which are specific to a given cell type, and are internalised by the target of interest. The principals described here may also be used to deliver other therapeutic oligonucleotides, including Antisense Oligonucleotides (ASO), Gapmers, microRNAs (miRNA) etc.

If you are trying to deliver siRNAs or other oligonucleotides; for therapeutic or research applications, or want to discuss the bespoke selection of aptamers for other applications, please get in touch.

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