The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
Biodistribution of Small Interfering RNA at the Organ and Cellular Levels after Lipid Nanoparticle-mediated Delivery
Open accessAbstract
Chemically stabilized small interfering RNA (siRNA) can be delivered systemically by intravenous injection of lipid nanoparticles (LNPs) in rodents and primates. The biodistribution and kinetics of LNP–siRNA delivery in mice at organ and cellular resolution have been studied using immunofluorescence (IF) staining and quantitative polymerase chain reaction (qPCR). At 0.5 and 2 hr post tail vein injection of Cy5-labeled siRNA encapsulated in LNP, the organ rank-order of siRNA levels is liver > spleen > kidney, with only negligible accumulation in duodenum, lung, heart, and brain. Similar conclusions were drawn by using qPCR to measure tissue siRNA levels as a secondary end point. siRNA levels in these tissues decreased by more than 10-fold after 24 hr. Within the liver, LNPs delivered siRNA to hepatocytes, Kupffer cells, and sinusoids in a time-dependent manner, as revealed by IF staining and signal quantitation methods established using OPERA/Columbus software. siRNA first accumulated in liver sinusoids and trafficked to hepatocytes by 2 hr post dose, corresponding to the onset of target mRNA silencing. Fluorescence in situ hybridization methods were used to detect both strands of siRNA in fixed tissues. Collectively, the authors have implemented a platform to evaluate biodistribution of siRNA across cell types and across tissues in vivo, with the objective of elucidating the pharmacokinetic and pharmacodynamic relationship to guide optimization of delivery vehicles.
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“The main off-target site of LNP-based platforms is the liver, more specifically hepatocytes and Kupffer cells (49, 50), and suppression of mRNAs in these cell types can be achieved by inserting miR122 and miR142 binding sites, respectively.”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [49]
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Metadata
- Authors
- Shi, B., Keough, E., Matter, A., Leander, K., Young, S., Carlini, E., Sachs, A. B., Tao, W., Abrams, M., Howell, B., & Sepp-Lorenzino, L.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Department of RNA Therapeutics (BS,EK,AM,KL,WT,MA,BH,LSL)
- Corresponding author
- Shi, Bin
- Venue
- Journal of Histochemistry & Cytochemistry
- Publisher
- SAGE Publications
- Published
- 2011-07-29
- Volume
- 59
- Issue
- 8
- Pages
- 727-740
- ISSN
- 0022-1554 (ISSN-L)
- 1551-5044
- PMC
- PMC3261601
- OpenAlex
- W1988464677
- Cited by
- 125
- References
- 78
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 10 · 2023: 7 · 2022: 14 · 2021: 10 · 2020: 10 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 11 · 2014: 8 · 2013: 13 · 2012: 3
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Histochemistry & Cytochemistry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- siRNA, lipid nanoparticles, systemic siRNA delivery, liver, hepatocytes, Kupffer cells, liver sinusoids, pharmacokinetics, pharmacodynamics, intravenous injection, fluorescence in situ hybridization
- MeSH terms
- SS-B Antigen, Animals, Autoantigens, Drug Carriers, Fluorescent Antibody Technique, Lipids, Ribonucleoproteins, RNA, Messenger, Tissue Distribution, In Situ Hybridization, Fluorescence, RNA, Small Interfering, Mice, Nanoparticles, Gene Knockdown Techniques
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