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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

Linda B Jensen, Joscha Griger, Broes Naeye UGent, Amir K Varkouhi, Koen Raemdonck UGent, Raymond Schiffelers, Twan Lammers, Gert Storm, Stefaan De Smedt UGent and Brian S Sproat, et al. (2012) PHARMACEUTICAL RESEARCH. 29(3). p.669-682
abstract
Tumor necrosis factor alpha (TNF-alpha) plays a key role in the progression of rheumatoid arthritis and is an important target for anti-rheumatic therapies. TNF-alpha 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-alpha siRNA with optimal efficacy and minimal off-target effects in vitro. TNF-alpha 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. 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. 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
NECROSIS-FACTOR-ALPHA, RHEUMATOID-ARTHRITIS, EPITHELIAL A549 CELLS, DRUG-DELIVERY SYSTEMS, COLLAGEN-INDUCED ARTHRITIS, BIODEGRADABLE DEXTRAN NANOGELS, SMALL INTERFERING RNA, TNF-alpha, siRNA, polymer, delivery, macrophages, IN-VIVO, DNA COMPLEXES, CANCER-CELLS
journal title
PHARMACEUTICAL RESEARCH
Pharm. Res.
volume
29
issue
3
pages
669 - 682
Web of Science type
Article
Web of Science id
000300457500005
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
4.742 (2012)
JCR rank
25/259 (2012)
JCR quartile
1 (2012)
ISSN
0724-8741
DOI
10.1007/s11095-011-0589-0
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2137021
handle
http://hdl.handle.net/1854/LU-2137021
date created
2012-06-08 11:21:47
date last changed
2012-06-19 11:52:45
@article{2137021,
  abstract     = {Tumor necrosis factor alpha (TNF-alpha) plays a key role in the progression of rheumatoid arthritis and is an important target for anti-rheumatic therapies. TNF-alpha 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-alpha siRNA with optimal efficacy and minimal off-target effects in vitro. 
TNF-alpha 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. 
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. 
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.},
  author       = {Jensen, Linda B and Griger, Joscha and Naeye, Broes and Varkouhi, Amir K and Raemdonck, Koen and Schiffelers, Raymond and Lammers, Twan and Storm, Gert and De Smedt, Stefaan and Sproat, Brian S and Nielsen, Hanne M and Foged, Camilla},
  issn         = {0724-8741},
  journal      = {PHARMACEUTICAL RESEARCH},
  keyword      = {NECROSIS-FACTOR-ALPHA,RHEUMATOID-ARTHRITIS,EPITHELIAL A549 CELLS,DRUG-DELIVERY SYSTEMS,COLLAGEN-INDUCED ARTHRITIS,BIODEGRADABLE DEXTRAN NANOGELS,SMALL INTERFERING RNA,TNF-alpha,siRNA,polymer,delivery,macrophages,IN-VIVO,DNA COMPLEXES,CANCER-CELLS},
  language     = {eng},
  number       = {3},
  pages        = {669--682},
  title        = {Comparison of polymeric siRNA nanocarriers in a murine LPS-activated macrophage cell line: gene silencing, toxicity and off-target gene expression},
  url          = {http://dx.doi.org/10.1007/s11095-011-0589-0},
  volume       = {29},
  year         = {2012},
}

Chicago
Jensen, Linda B, Joscha Griger, Broes Naeye, Amir K Varkouhi, Koen Raemdonck, Raymond Schiffelers, Twan Lammers, et al. 2012. “Comparison of Polymeric siRNA Nanocarriers in a Murine LPS-activated Macrophage Cell Line: Gene Silencing, Toxicity and Off-target Gene Expression.” Pharmaceutical Research 29 (3): 669–682.
APA
Jensen, L. B., Griger, J., Naeye, B., Varkouhi, A. K., Raemdonck, K., Schiffelers, R., Lammers, T., et al. (2012). Comparison of polymeric siRNA nanocarriers in a murine LPS-activated macrophage cell line: gene silencing, toxicity and off-target gene expression. PHARMACEUTICAL RESEARCH, 29(3), 669–682.
Vancouver
1.
Jensen LB, Griger J, Naeye B, Varkouhi AK, Raemdonck K, Schiffelers R, et al. Comparison of polymeric siRNA nanocarriers in a murine LPS-activated macrophage cell line: gene silencing, toxicity and off-target gene expression. PHARMACEUTICAL RESEARCH. 2012;29(3):669–82.
MLA
Jensen, Linda B, Joscha Griger, Broes Naeye, et al. “Comparison of Polymeric siRNA Nanocarriers in a Murine LPS-activated Macrophage Cell Line: Gene Silencing, Toxicity and Off-target Gene Expression.” PHARMACEUTICAL RESEARCH 29.3 (2012): 669–682. Print.