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Influence of Cationic Lipid Composition on Gene Silencing Properties of Lipid Nanoparticle Formulations of siRNA in Antigen-Presenting Cells
- Source :
- Molecular Therapy
- Publication Year :
- 2011
- Publisher :
- Nature Publishing Group, 2011.
-
Abstract
- Lipid nanoparticles (LNPs) are currently the most effective in vivo delivery systems for silencing target genes in hepatocytes employing small interfering RNA. Antigen-presenting cells (APCs) are also potential targets for LNP siRNA. We examined the uptake, intracellular trafficking, and gene silencing potency in primary bone marrow macrophages (bmMΦ) and dendritic cells of siRNA formulated in LNPs containing four different ionizable cationic lipids namely DLinDAP, DLinDMA, DLinK-DMA, and DLinKC2-DMA. LNPs containing DLinKC2-DMA were the most potent formulations as determined by their ability to inhibit the production of GAPDH target protein. Also, LNPs containing DLinKC2-DMA were the most potent intracellular delivery agents as indicated by confocal studies of endosomal versus cytoplamic siRNA location using fluorescently labeled siRNA. DLinK-DMA and DLinKC2-DMA formulations exhibited improved gene silencing potencies relative to DLinDMA but were less toxic. In vivo results showed that LNP siRNA systems containing DLinKC2-DMA are effective agents for silencing GAPDH in APCs in the spleen and peritoneal cavity following systemic administration. Gene silencing in APCs was RNAi mediated and the use of larger LNPs resulted in substantially reduced hepatocyte silencing, while similar efficacy was maintained in APCs. These results are discussed with regard to the potential of LNP siRNA formulations to treat immunologically mediated diseases.
- Subjects :
- Small interfering RNA
Blotting, Western
Antigen-Presenting Cells
02 engineering and technology
Biology
03 medical and health sciences
Mice
In vivo
RNA interference
Bone Marrow
Cations
Drug Discovery
Genetics
Gene silencing
Animals
Gene Silencing
RNA, Small Interfering
Antigen-presenting cell
Molecular Biology
Cells, Cultured
030304 developmental biology
Pharmacology
0303 health sciences
Liposome
Macrophages
Glyceraldehyde-3-Phosphate Dehydrogenases
Dendritic Cells
021001 nanoscience & nanotechnology
Flow Cytometry
Molecular biology
Lipids
Endocytosis
3. Good health
Cell biology
Mice, Inbred C57BL
Liver
Liposomes
Systemic administration
Hepatocytes
Molecular Medicine
Leukocyte Common Antigens
Nanoparticles
Original Article
RNA Interference
Target protein
0210 nano-technology
Subjects
Details
- Language :
- English
- ISSN :
- 15250024 and 15250016
- Volume :
- 19
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....efe8255d4af35f8e265d89fd0759f9e8