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Functional TNFα gene silencing mediated by polyethyleneimine/TNFα siRNA nanocomplexes in inflamed colon.
- Source :
-
Biomaterials [Biomaterials] 2011 Feb; Vol. 32 (4), pp. 1218-28. - Publication Year :
- 2011
-
Abstract
- During inflammatory bowel disease, TNFα is the major pro-inflammatory cytokine mainly secreted from macrophages and dendritic cells. Here, we have demonstrated that TNFα siRNA/polyethyleneimine loaded into polylactide at an optimal concentration of 20 g/L nanoparticles covered with polyvinyl alcohol are efficiently taken up by inflamed macrophages and inhibit TNFα secretion by the macrophages. Those nanoparticles have a diameter of ∼380 nm and zeta potential of -8 mV at pH 7.2, and are non-cytotoxic. Complexation, interactions and protection from RNAse between TNFα siRNA and polyethyleneimine were higher than those using chitosan. Importantly, complexation between TNFα siRNA and polyethyleneimine facilitated higher rates of siRNA loading into nanoparticles, compared to Chi or free siRNA mixed with Lipofectamine. Oral administration of encapsulated TNFα siRNA-loaded nanoparticles specifically reduced the TNFα expression/secretion in colonic tissue in LPS-treated mice. In conclusion, we have shown: (1) that proposed TNFα siRNA-loaded NPs are prepared via a non-denaturing synthetic process; (2) a high encapsulation rate of TNFα siRNA complexed to polyethyleneimine into NPs; (3) effective enzymatic protection of TNFα siRNA by polyethyleneimine; (4) non-cytotoxicity and biodegradability of nanoparticles loaded with polyethyleneimine/TNFα siRNA; and (5) in vitro and in vivo significant anti-inflammatory effects at low TNFα siRNA dose that is specific and restricted to the colonic cells. Our results collectively indicate that polyethyleneimine/TNFα siRNA nanocomplexes represent an efficient therapeutic option for diseases such as IBD.<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Humans
Inflammatory Bowel Diseases metabolism
Inflammatory Bowel Diseases pathology
Inflammatory Bowel Diseases therapy
Macrophages metabolism
Materials Testing
Mice
Nanoparticles therapeutic use
Polyethyleneimine metabolism
RNA, Small Interfering chemistry
RNA, Small Interfering genetics
Tumor Necrosis Factor-alpha metabolism
Colon metabolism
Colon pathology
Gene Silencing
Nanoparticles chemistry
Polyethyleneimine chemistry
RNA, Small Interfering metabolism
Tumor Necrosis Factor-alpha genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5905
- Volume :
- 32
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biomaterials
- Publication Type :
- Academic Journal
- Accession number :
- 20970849
- Full Text :
- https://doi.org/10.1016/j.biomaterials.2010.09.062