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Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Biol+Chem 2016 ; 291 (12): 6433-46 Nephropedia Template TP
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Self-assembled Micelle Interfering RNA for Effective and Safe Targeting of Dysregulated Genes in Pulmonary Fibrosis* #MMPMID26817844
Yoon PO; Park JW; Lee CM; Kim SH; Kim HN; Ko Y; Bae SJ; Yun S; Park JH; Kwon T; Kim WS; Lee J; Lu Q; Kang HR; Cho WK; Elias JA; Yang JS; Park HO; Lee K; Lee CG
J Biol Chem 2016[Mar]; 291 (12): 6433-46 PMID26817844show ga
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 ?m) on murine peripheral blood mononuclear cells did not cause any significant elaboration of innate immune cytokines such as TNF-?, 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-? 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-?-stimulated collagen accumulation in the lung and substantially restored the lung function of TGF-? 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.