Cellular uptake and intracellular release are major obstacles to the therapeutic application of siRNA: novel options by phosphorothioate-stimulated delivery

Abstract

The cellular uptake of oligomeric nucleic acid-based tools and drugs including small-interfering RNA (siRNA) represents a major technical hurdle for the biologic effectiveness and therapeutic success in vivo. Subsequent to cellular delivery it is crucial to direct siRNA to the cellular location where it enters the RNA interference pathway. Here the authors summarise evidence that functionally active siRNA represents a minor fraction in the order of 1% of total siRNA inside a given target cell. Exploiting possibilities of steering intracellular release or trafficking of siRNA bears the potential of substantially increasing the biological activity of siRNA. The recently described phosphorothioate stimulated cellular delivery of siRNA makes use of the caveolar system ending in the Golgi apparatus, which contrasts all other known delivery systems. Therefore, it represents an attractive alternative to study whether promoted intracellular release is related to increased target suppression and, thus, increased phenotypic biologic effectiveness.

Keywords::

• caveolae
• cellular uptake
• delivery
• intracellular release
• phosphorothioate
• siRNA

Acknowledgements

The authors wish to thank S Laufer and T Restle for helpful discussions. This work was supported by grants of the Werner und Klara Kreitz-Stiftung, Kiel, and the Medical Faculty of the Universität zu Lübeck to A Mescalchin (FKZ: A26:2007) and M Overhoff (FKZ: A28:2007).

The authors would like to highlight to the readers that very recent observations indicate that the PS-stimulated caveosomal uptake of siRNA might also involve perinuclear compartments other than the Golgi apparatus.

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