Enteric nanomedicine for targeted silencing of NF-kappa B gene products in colitis ulcerosa

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In the preceding research project, we have shown that calcium phosphate nanoparticles carrying siRNA against the p65 NF-kB protein are able to revert the increased p65 NF-kB gene and protein expression in inflamed monocytes and other leucocytes in vitro. In the next step, we assessed the therapeutic efficacy of the calcium phosphate nanoparticles carrying siRNA in a mouse model of colitis, since: First, colitis ulcerosa is a chronic inflammatory bowel disease with high incidence in developed countries. Second, the current treatment modalities do not lead to a complete cure. Third, colitis ulcerosa is known to elicit a constitutive NF-kB activation. In the murine model of colitis ulcerosa, the intravenous application of our calcium phosphate nanoparticles carrying p65 siRNA led only to alleviated effects of inflammation. We attribute this finding to the fact that only a small part of the functional nanoparticles reached the colon (only 2% of the injected dose). Therefore, in this project, we build up on our experience in the preceding project and provide an approach based on siRNA and gold nanoparticles (denoted as siRNA-Au-NPs), which can be further developed for the treatment of colitis ulcerosa via rectal application. We expect that the Au-NPs are excellent siRNA-carriers for the treatment of colitis ulcerosa and elicit a good accessibility to pro-inflammatory cells of the inflamed colon. Since we have shown that anti-p65 siRNA encapsulated into calcium phosphate nanoparticles successfully alleviated colitis in mice, we will continue targeting p65 NF-kappa B translation by specific siRNAs. From the experimental point of view, we will prepare ultra-small gold nanoparticles with a high loading of siRNA in different dispersion media, determine the siRNA bioactivity, the retention at the inflamed mucosa, assess the anti-inflammatory potential in the colon and unveil the mechanisms of action. Consequently, this siRNA-based nanomedicine could provide an effective tool for the treatment of colitis ulcerosa.