Abstract
Photochemical internalization (PCI) has been employed as a tool for site-specific intracellular delivery of a variety of molecules. In this study, for the first time, PCI has been employed to facilitate the endosomal escape of small interfering RNA (siRNA) molecules, which are the functional mediators of RNA interference (RNAi). In order to interact with the machinery that will induce post-transcriptional gene silencing, siRNA molecules need to enter the cytoplasm of the cells. This study shows that one of the important rate-limiting steps of siRNA silencing efficiency is the ability of siRNA molecules and/or complexes to escape from the endosomes into the cytosol of the cells. The target of this study, the epidermal growth factor receptor (EGFR), is known as an attractive target for cancer therapy. In this study, a 10-fold increased efficiency in knockdown of the EGFR protein was obtained when anti-EGFR siRNA treatment was combined with PCI as compared to siRNA treatment alone. The fact that this combined treatment resulted in a stronger silencing efficiency indicates that lower doses of siRNA can be used when PCI is employed to augment siRNA delivery. Lowering doses of siRNA would prevent saturation of the RNAi machinery and reduce off-target effects. In addition, local illumination of target tissue would only induce PCI in the desired cells, which can further increase the specificity of the treatment, supporting PCI as an attractive strategy to improve siRNA silencing efficiency.
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More From: Biochimica et Biophysica Acta (BBA) - Biomembranes
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