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Self-assembled Micelle Interfering RNA for Effective and Safe Targeting of Dysregulated Genes in Pulmonary Fibrosis
- Source :
- The Journal of biological chemistry. 291(12)
- Publication Year :
- 2015
-
Abstract
- The siRNA silencing approach has long been used as a method to regulate the expression of specific target genes in vitro and in vivo. However, the effectiveness of delivery and the nonspecific immune-stimulatory function of siRNA are the limiting factors for therapeutic applications of siRNAs. To overcome these limitations, we developed self-assembled micelle inhibitory RNA (SAMiRNA) nanoparticles made of individually biconjugated siRNAs with a hydrophilic polymer and lipid on their ends and characterized their stability, immune-stimulatory function, and in vivo silencing efficacy. SAMiRNAs form very stable nanoparticles with no significant degradation in size distribution and polydispersity index over 1 year. Overnight incubation of SAMiRNAs (3 μm) on murine peripheral blood mononuclear cells did not cause any significant elaboration of innate immune cytokines such as TNF-α, IL-12, or IL-6, whereas unmodified siRNAs or liposomes or liposome complexes significantly stimulated the expression of these cytokines. Last, the in vivo silencing efficacy of SAMiRNAs was evaluated by targeting amphiregulin and connective tissue growth factor in bleomycin or TGF-β transgenic animal models of pulmonary fibrosis. Intratracheal or intravenous delivery two or three times of amphiregulin or connective tissue growth factor SAMiRNAs significantly reduced the bleomycin- or TGF-β-stimulated collagen accumulation in the lung and substantially restored the lung function of TGF-β transgenic mice. This study demonstrates that SAMiRNA nanoparticle is a less toxic, stable siRNA silencing platform for efficient in vivo targeting of genes implicated in the pathogenesis of pulmonary fibrosis.
- Subjects :
- 0301 basic medicine
Male
Small interfering RNA
EGF Family of Proteins
medicine.medical_treatment
Pulmonary Fibrosis
Connective tissue
Biology
Bleomycin
Biochemistry
Amphiregulin
03 medical and health sciences
chemistry.chemical_compound
In vivo
Pulmonary fibrosis
medicine
Gene silencing
Animals
Tissue Distribution
Gene Regulation
RNA, Small Interfering
Molecular Biology
Lung
Cells, Cultured
Micelles
Growth factor
Connective Tissue Growth Factor
Cell Biology
Genetic Therapy
medicine.disease
Molecular biology
Cell biology
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
chemistry
Gene Knockdown Techniques
Nanoparticles
Female
RNA Interference
Collagen
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 291
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....2f9993d008462c39a451fb08aa890525