Development of lipid nanoparticle formulations of siRNA for hepatocyte gene silencing following subcutaneous administration
Abstract
Recently developed lipid nanoparticle (LNP) formulations of siRNA have proven to be effective agents for hepatocyte gene silencing following intravenous administration with at least three LNP-siRNA formulations in clinical trials. The aim of this work was to develop LNP-siRNA systems for hepatocyte gene silencing that can be administered subcutaneously (s.c.). Three parameters were investigated, namely LNP size, residence time of the polyethylene glycol (PEG)-lipid coating and the influence of hepatocyte-specific targeting ligands. LNP sizes were varied over the range of 30 to 115 nm in diameter and PEG-lipid that dissociates rapidly (PEG-DMG) and slowly (PEG-DSG) were employed. In mice, results show that large (~80 nm) LNP exhibited limited accumulation in the liver and poor Factor VII (FVII) gene silencing at 1mg siRNA/kg body weight. Conversely, small (~30 nm) LNP systems showed maximal liver accumulation yet still had minimal activity. Interestingly, intermediate size (~45 nm) LNP containing PEG-DSG exhibited nearly equivalent liver accumulation as the smaller systems following s.c. administration but reduced FVII levels by 80% at 1mg siRNA/kg body weight. Smaller systems (~35 nm diameter) containing either PEG-DMG or PEG-DSG were less active; however addition of 0.5 mol.% of a GalNAc-PEG lipid to these smaller systems improved activity to levels similar to that observed for the ~45 nm diameter systems. In summary, this work shows that appropriately designed LNP-siRNA sys…
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In mice, nanoparticles densely coated with PEG measuring up to 200 nm in diameter were able to spread within brain tissue, a size range achievable for LNPs.
“In mice, nanoparticles densely coated with PEG measuring up to 200 nm in diameter were able to spread within brain tissue (28), a size range achievable for LNPs (9, 29).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [29]
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“As the lipid composition employed here is different than used previously, we examined the size distribution achieved for LNP– siRNA systems composed of DMAP-BLP, DSPC, cholesterol and PEG- DMG in the molar ratios 50:10:(39.75 − x):(0.25 + x), where x was varied from 0 to 4.75, encapsulating siRNA at a N/P (+/-) charge…”
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- Authors
- Chen, S., Tam, Y. Y. C., Lin, P. J. C., Leung, A. K. K., Tam, Y. K., & Cullis, P. R.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Cullis, Pieter R.
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 196
- Pages
- 106-112
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2112951256
- Cited by
- 160
- References
- 5
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 19 · 2023: 20 · 2022: 18 · 2021: 18 · 2020: 10 · 2019: 15 · 2018: 8 · 2017: 5 · 2016: 9 · 2015: 7
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes for Health Research (CIHR FRN 111627)
- Alnylam Pharmaceuticals
- 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 › Advanced Drug Delivery Systems
- Keywords
- lipid nanoparticles, siRNA, subcutaneous administration, factor VII, liver accumulation, siRNA delivery
- MeSH terms
- Animals, Chemistry, Pharmaceutical, Factor VII, Female, Lipids, Mice, Inbred C57BL, Tissue Distribution, Drug Delivery Systems, Gene Silencing, Hepatocytes, RNA, Small Interfering, Mice, Nanoparticles, Infusions, Subcutaneous
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