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pH-labile PEGylation of siRNA-loaded lipid nanoparticle improves active targeting and gene silencing activity in hepatocytes

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Title: pH-labile PEGylation of siRNA-loaded lipid nanoparticle improves active targeting and gene silencing activity in hepatocytes
Authors: Hashiba, Kazuki Browse this author
Sato, Yusuke Browse this author →KAKEN DB
Harashima, Hideyoshi Browse this author →KAKEN DB
Keywords: Maleic anhydride
pH-labile
PEGylation
siRNA delivery
Active target
Lipid nanoparticles
Issue Date: 28-Sep-2017
Publisher: Elsevier
Journal Title: Journal of controlled release
Volume: 262
Start Page: 239
End Page: 246
Publisher DOI: 10.1016/j.jconrel.2017.07.046
PMID: 28774839
Abstract: Lipid nanoparticles (LNPs) are one of the promising technologies for the in vivo delivery of short interfering RNA (siRNA). Modifying LNPs with polyethyleneglycol (PEG) is widely used to inhibit non-specific interactions with serum components in the blood stream, and is a useful strategy for maximizing the efficiency of active targeting. However, it is a widely accepted fact that PEGylation of the LNP surface strongly inhibits fusion between LNPs and endosomal membranes, resulting in poor cytosolic siRNA delivery, a process that is referred to as the 'PEGdilemma'. In the present study, in an attempt to overcome this problem, siRNA-loaded LNPs were modified with PEG through maleic anhydride, a pH-labile linkage. The in vitro, suppression of cationic charge, stealth function at physiological pH up to 1 h and the rapid desorption of PEG and restoration of fusogenic activity under slightly acidic conditions (within only 2 min) were achieved by PEG modification of the LNPs through maleic anhydride. In vivo, PEG modification through maleic anhydride resulted in a dramatic improvement in the targeting capability of the active targeting of ligand (N-acetyl-D-galactosamine)-modified LNPs to hepatocytes, with an approximately 14-fold increase in gene silencing activity in factor 7 model mice. Taken together, the maleic an-hydride-mediated pH-labile PEGylation of the active targeting LNPs is a useful strategy for achieving the specific and efficient delivery of siRNAs in vivo.
Rights: ©2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
http://creativecommons.org/licenses/by-nc-nd/4.0/
Type: article (author version)
URI: http://hdl.handle.net/2115/71549
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 佐藤 悠介

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