| Noninvasive imaging of lipid nanoparticle-mediated systemic delivery of small-interfering RNA to the liver. | |
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MedLine Citation:
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PMID: 20628357 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mouse models with liver-specific expression of firefly luciferase were developed that enable a noninvasive and longitudinal assessment of small-interfering RNA (siRNA)-mediated gene silencing in hepatocytes of live animals via bioluminescence imaging. Using these models, a set of lipid nanoparticles (LNPs) with different compositions of cationic lipids, polyethylene glycol (PEG), and cholesterol, were tested for their abilities in delivering a luciferase siRNA to the liver via systemic administration. A dose-dependent luciferase knockdown by LNP/siRNA assemblies was measured by in vivo bioluminescence imaging, which correlated well with the results from parallel ex vivo analyses of luciferase mRNA and protein levels in the liver. RNA interference (RNAi)-mediated target silencing was further confirmed by the detection of RNAi-specific target mRNA cleavage. A single dose of LNP02L at 3 mg/kg (siRNA) caused 90% reduction of luciferase expression and the target repression lasted for at least 10 days. With identical components, LNPs containing 2% PEG are more potent than those with 5.4% PEG. Our results demonstrate that these liver-luciferase mouse models provide a powerful tool for a high-throughput evaluation of hepatic delivery platforms by noninvasive imaging and that the molar ratio of PEG lipid can affect the efficacy of LNPs in silencing liver targets via systemic administration. |
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Authors:
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Weikang Tao; Joseph P Davide; Mingmei Cai; Guo-Jun Zhang; Victoria J South; Andrea Matter; Bruce Ng; Ye Zhang; Laura Sepp-Lorenzino |
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Publication Detail:
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Type: Journal Article Date: 2010-07-13 |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: 18 ISSN: 1525-0024 ISO Abbreviation: Mol. Ther. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-02 Completed Date: 2010-12-22 Revised Date: 2011-09-13 |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1657-66 Citation Subset: IM |
Affiliation:
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Department of RNA Therapeutics, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. weikang_tao@merck.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Fluorescent Antibody Technique Gene Silencing / physiology Lipids / chemistry* Liver / enzymology, metabolism* Luciferases / genetics Mice Nanoparticles / administration & dosage*, chemistry* RNA, Small Interfering / administration & dosage*, genetics* |
| Chemical | |
Reg. No./Substance:
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0/Lipids; 0/RNA, Small Interfering; EC 1.13.12.-/Luciferases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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