alexa Barriers to successful delivery of short interfering RNA after systemic administration.
Pharmaceutical Sciences

Pharmaceutical Sciences

Journal of Pharmacogenomics & Pharmacoproteomics

Author(s): White PJ

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Abstract 1. RNA interference in vivo has tremendous potential, both with respect to the elucidation of protein function in animals and as a therapeutic platform in humans. In vitro, short interfering RNA (siRNA) has been shown to completely silence gene expression in mammalian cells at low picomolar concentrations. 2. Although many good publications have shown specific silencing to occur in vivo, there are few that have transferred the combination of maximal efficacy and high potency to this setting. The present review considers the biological barriers that limit the movement of siRNA from vascular lumen to target cell cytoplasm and the strategies that have been used to overcome them. 3. Intravenous administration of siRNA results in rapid, extensive removal of siRNA from the blood via renal excretion, tissue distribution and nuclease degradation. Movement across vascular capillaries appears to be a limiting factor in some cases; few examples of silencing have been reported in organs with a conventional capillary endothelium. 4. Cellular uptake and endosomal trapping are significant barriers, but can be overcome using strategies such as antibody mediated cellular uptake or polyethyleneimine-mediated endosomal escape. This article was published in Clin Exp Pharmacol Physiol and referenced in Journal of Pharmacogenomics & Pharmacoproteomics

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