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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2016 ; 291
(12
): 6433-46
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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
PMID26817844
show 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.