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Self-assembled Micelle Interfering RNA for Effective and Safe Targeting of Dysregulated Genes in Pulmonary Fibrosis

Authors :
Won-Kyung Cho
Han Oh Park
Chun Geun Lee
Qing Lu
Kyuhong Lee
Jin Wook Park
Pyoung Oh Yoon
Han Na Kim
Sung-Hwan Kim
Hye Ryun Kang
Jun Hong Park
Joo Sung Yang
Jack A. Elias
Sung-Il Yun
Woo-Seok Kim
Youngho Ko
Chang-Min Lee
Bae Seon Joo
Tae-woo Kwon
Ji-Young Lee
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.

Details

ISSN :
1083351X
Volume :
291
Issue :
12
Database :
OpenAIRE
Journal :
The Journal of biological chemistry
Accession number :
edsair.doi.dedup.....2f9993d008462c39a451fb08aa890525