Cited by 125RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvancements in Transdermal Drug Delivery

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Biodistribution of Small Interfering RNA at the Organ and Cellular Levels after Lipid Nanoparticle-mediated Delivery

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Shi, Bin, Keough, Ed, Matter, Andrea, Leander, Karen, Young, Stephanie, Carlini, Ed, Sachs, Alan B., Tao, Weikang, Abrams, Marc, Howell, Bonnie, Sepp-Lorenzino, Laura·2011·Journal of Histochemistry & Cytochemistry

DOI 10.1369/0022155411410885PMC PMC3261601

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Abstract

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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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
ORCID: Shi, Bin
Matter, Andrea
Howell, Bonnie
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
DOI: 10.1369/0022155411410885
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
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
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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Biodistribution of Small Interfering RNA at the Organ and Cellular Levels after Lipid Nanoparticle-mediated Delivery

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