Cited by 176RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryBarrier Structure and Function Studies

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shRNA and siRNA delivery to the brain

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Pardridge, William M.·2007·Advanced Drug Delivery Reviews

DOI 10.1016/j.addr.2007.03.008PMC PMC3572210

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Abstract

The limiting factor in in vivo RNA interference (RNAi) is delivery. Drug delivery methods that are effective in cell culture may not be practical in vivo for intravenous RNAi applications. Nucleic acid drugs are highly charged and do not cross cell membranes by free diffusion. Therefore, the in vivo delivery of RNAi therapeutics must use targeting technology that enables the RNAi therapeutic to traverse biological membrane barriers in vivo. For RNAi of the brain, the nucleic acid-based drug must first cross the brain capillary endothelial wall, which forms the blood-brain barrier (BBB) in vivo, and then traverses the brain cell plasma membrane. Similar to the delivery of non-viral gene therapies, plasmid DNA encoding for short hairpin RNA (shRNA) may be delivered to the brain following intravenous administration with pegylated immunoliposomes (PILs). The plasmid DNA is encapsulated in a 100 nm liposome, which is pegylated, and conjugated with receptor specific targeting monoclonal antibodies (MAb). Weekly, intravenous RNAi with PILs enables a 90% knockdown of the human epidermal growth factor receptor, which results in a 90% increase in survival time in mice with intra-cranial brain cancer. Similar to the delivery of antisense agents, short interfering RNAi (siRNA) duplexes can be delivered with the combined use of targeting MAb's and avidin-biotin technology. The siRNA is mono-biotinylated in parallel with the production of a conjugate of the targeting MAb and streptavidin. Intravenous RNAi requires the combined use of RNAi technology and a drug targeting technology that is effective in vivo.

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Authors: Pardridge, W. M.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Pardridge, William M.
ORCID: Pardridge, William M.
Venue: Advanced Drug Delivery Reviews
Publisher: Elsevier BV
Published: 2007-03
Volume: 59
Issue: 2-3
Pages: 141-152
ISSN: 0169-409X (ISSN-L)
DOI: 10.1016/j.addr.2007.03.008
PMC: PMC3572210
OpenAlex: W2031687291
Cited by: 176
References: 59
Citations by year: 2025: 4 · 2024: 6 · 2023: 9 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 10 · 2018: 4 · 2017: 10 · 2016: 6 · 2015: 8 · 2014: 3 · 2013: 18 · 2012: 12
FWCI: 1.23
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Advanced Drug Delivery Reviews (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Neurological Disorders and Stroke (R01NS053540)
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 › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: RNA interference, shRNA delivery, siRNA delivery, brain, blood-brain barrier, monoclonal antibody targeting, intravenous administration, epidermal growth factor receptor, brain cancer, nucleic acid drug delivery, membrane crossing
MeSH terms: Animals, Brain, Carrier Proteins, Humans, Plasmids, Reproducibility of Results, Drug Delivery Systems, RNA, Small Interfering

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