Ghosn Bilal, Singh Ankur, Li Mu, Vlassov Alexander V, Burnett Chris, Puri Nitin, Roy Krishnendu
Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712-0238, USA.
Oligonucleotides. 2010 Jun;20(3):163-72. doi: 10.1089/oli.2010.0235.
Despite high specificity and potency, small interfering RNA (siRNA)-based therapeutics have been limited by their poor biostability and intracellular penetration. Thus, effective nanocarriers that can protect and efficiently deliver siRNA to target cells in vivo are needed. Here we report on the efficiency of imidazole-modified chitosan (chitosan-imidazole-4-acetic acid [IAA])-siRNA nanoparticles to mediate gene silencing after administration via either intravenous (i.v.) or intranasal (i.n.) routes. Poly(ethylene glycol) (PEG)ylated nanoparticles for i.v. delivery demonstrated significant knockdown of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme in both lung and liver at as low as 1 mg/kg siRNA dose. In addition, the efficient, dose-dependent silencing of apolipoprotein B in the liver was also shown. For i.n. delivery, significant silencing of GAPDH protein expression was seen in the lungs with only 0.5 mg/kg/day siRNA delivered over 3 consecutive days. In summary, imidazole-modified chitosan-IAA nanoparticles are potentially effective carriers for siRNA delivery.
尽管具有高特异性和高效性，但基于小干扰RNA（siRNA）的疗法一直受到其生物稳定性差和细胞内穿透性低的限制。因此，需要能够在体内保护并有效将siRNA递送至靶细胞的有效纳米载体。在此，我们报告了咪唑修饰的壳聚糖（壳聚糖-咪唑-4-乙酸[IAA]）-siRNA纳米颗粒经静脉内（i.v.）或鼻内（i.n.）途径给药后介导基因沉默的效率。用于静脉内递送的聚乙二醇（PEG）化纳米颗粒在低至1 mg/kg siRNA剂量时，在肺和肝中均显示出甘油醛-3-磷酸脱氢酶（GAPDH）酶的显著敲低。此外，还显示出肝脏中载脂蛋白B的高效、剂量依赖性沉默。对于鼻内递送，连续3天仅递送0.5 mg/kg/天的siRNA，肺部可见GAPDH蛋白表达的显著沉默。总之，咪唑修饰的壳聚糖-IAA纳米颗粒是用于siRNA递送的潜在有效载体。
