Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I

被引:142
作者
Kim, Soo In
Shin, Duckhyang
Choi, Tae Hyun
Lee, Jong Chan
Cheon, Gi-Jeong
Kim, Ki-Yong
Park, Mahnhoon
Kim, Meehyein
机构
[1] Mogam Biotechnol Res Inst, Immunol & Virol Grp, Yongin 449913, Kyonggi Do, South Korea
[2] Korea Inst Radiol & Med Sci, Emergency Med Team, Seoul, South Korea
[3] Korea Inst Radiol & Med Sci, Nucl Med Lab, Seoul, South Korea
[4] Green Cross Co, Prot Res Lab, Yongin, South Korea
关键词
D O I
10.1038/sj.mt.6300168
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Tissue-targeted delivery of small interfering RNA (siRNA) must be achieved before RNA interference (RNAi) technology can be used in practical therapeutic approaches. In this study, the potential of apolipoprotein A-I (apo A-I) for the systemic delivery of nucleic acids to the liver is demonstrated using real-time in vivo imaging. As a proof of concept, synthetic siRNAs against hepatitis B virus (HBV) were formulated into complexes of apo A-I and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (DTC-Apo) and injected intravenously (IV) into a mouse model carrying replicating HBV. We show that administration of these nanoparticles can significantly reduce viral protein expression by receptor-mediated endocytosis. The advantages of the apo A-I-mediated siRNA delivery method are its liver specificity, its effectiveness at low doses (<= 2 mg/kg) in only a single treatment, and its persistent antiviral effect up to 8 days. The liver-targeted gene silencing was also shown by in vivo images, in which bioluminescent signals emitted from the liver were efficiently reduced after IV administration of luciferase-specific siRNA and DTC-Apo lipoplex. Thus, our unique approach to siRNA delivery creates a foundation for the development of a new class of promising therapeutics against hepatitis viruses or hepatocyte genes related to tumor growth.
引用
收藏
页码:1145 / 1152
页数:8
相关论文
共 30 条
[1]   LABELING OF PROTEINS TO HIGH SPECIFIC RADIOACTIVITIES BY CONJUGATION TO A I-125-CONTAINING ACYLATING AGENT - APPLICATION TO RADIOIMMUNOASSAY [J].
BOLTON, AE ;
HUNTER, WM .
BIOCHEMICAL JOURNAL, 1973, 133 (03) :529-538
[2]   Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells [J].
Elbashir, SM ;
Harborth, J ;
Lendeckel, W ;
Yalcin, A ;
Weber, K ;
Tuschl, T .
NATURE, 2001, 411 (6836) :494-498
[3]  
GLASS C, 1985, J BIOL CHEM, V260, P744
[4]   RNA interference [J].
Hannon, GJ .
NATURE, 2002, 418 (6894) :244-251
[5]  
HUNTER R, 1970, P SOC EXP BIOL MED, V133, P989
[6]   Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA [J].
Judge, AD ;
Sood, V ;
Shaw, JR ;
Fang, D ;
McClintock, K ;
MacLachlan, I .
NATURE BIOTECHNOLOGY, 2005, 23 (04) :457-462
[7]   Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo [J].
Judge, AD ;
Bola, G ;
Lee, ACH ;
MacLachlan, I .
MOLECULAR THERAPY, 2006, 13 (03) :494-505
[8]  
Kim SI, 2003, CANCER RES, V63, P6458
[9]   Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery [J].
Landen, CN ;
Chavez-Reyes, A ;
Bucana, C ;
Schmandt, R ;
Deavers, MT ;
Lopez-Berestein, G ;
Sood, AK .
CANCER RESEARCH, 2005, 65 (15) :6910-6918
[10]   Production and characterization of a reconstituted high density lipoprotein for therapeutic applications [J].
Lerch, PG ;
Fortsch, V ;
Hodler, G ;
Bolli, R .
VOX SANGUINIS, 1996, 71 (03) :155-164