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Comparison of polymeric siRNA nanocarriers in a murine LPS-activated macrophage cell line: gene silencing, toxicity and off-target gene expression.
- Source :
-
Pharmaceutical research [Pharm Res] 2012 Mar; Vol. 29 (3), pp. 669-82. Date of Electronic Publication: 2011 Oct 05. - Publication Year :
- 2012
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Abstract
- Purpose: Tumor necrosis factor α (TNF-α) plays a key role in the progression of rheumatoid arthritis and is an important target for anti-rheumatic therapies. TNF-α expression can be silenced with small interfering RNA (siRNA), but efficacy is dependent on efficient and safe siRNA delivery vehicles. We aimed to identify polymeric nanocarriers for anti-TNF-α siRNA with optimal efficacy and minimal off-target effects in vitro.<br />Methods: TNF-α silencing with polymeric siRNA nanocarriers was compared in lipopolysaccharide-activated RAW 264.7 macrophages by real-time reverse transcription (RT)-PCR. Expression of non-target genes involved in inflammation, apoptosis, and cell cycle progression was determined by RT-PCR, toxicity evaluated by propidium iodide and annexin V staining.<br />Results: PAMAM dendrimers (G4 and G7) and dextran nanogels mediated remarkably high concentration-dependent gene silencing and low toxicity; dioleoyltrimethylammoniumpropane-modified poly(DL-lactide-co-glycolide acid) nanoparticles, thiolated, trimethylated chitosan and poly[(2-hydroxypropyl)methacrylamide 1-methyl-2-piperidine methanol] polyplexes were less efficient transfectants. There were minor changes in the regulation of off-target genes, mainly dependent on nanocarrier and siRNA concentration.<br />Conclusions: Dextran nanogels and PAMAM dendrimers mediated high gene silencing with minor toxicity and off-target transcriptional changes and are therefore expected to be suitable siRNA delivery systems in vivo.
- Subjects :
- Animals
Cell Line
Dendrimers metabolism
Dextrans metabolism
Gene Expression
Mice
Nanogels
Polyethylene Glycols metabolism
Polyethyleneimine metabolism
RNA, Small Interfering genetics
Drug Carriers metabolism
Gene Silencing
Lipopolysaccharides metabolism
Macrophages metabolism
RNA, Small Interfering administration & dosage
Tumor Necrosis Factor-alpha genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1573-904X
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Pharmaceutical research
- Publication Type :
- Academic Journal
- Accession number :
- 21971827
- Full Text :
- https://doi.org/10.1007/s11095-011-0589-0