title: Influence of Polyethylene Glycol Lipid Desorption Rates on Pharmacokinetics and Pharmacodynamics of siRNA Lipid Nanoparticles.
abstract: Lipid nanoparticles (LNPs) encapsulating short interfering RNAs that target hepatic genes are advancing through clinical trials, and early results indicate the excellent gene silencing observed in rodents and nonhuman primates also translates to humans. This success has motivated research to identify ways to further advance this delivery platform. Here, we characterize the polyethylene glycol lipid (PEG-lipid) components, which are required to control the self-assembly process during formation of lipid particles, but can negatively affect delivery to hepatocytes and hepatic gene silencing in vivo. The rate of transfer from LNPs to plasma lipoproteins in vivo is measured for three PEG-lipids with dialkyl chains 14, 16, and 18 carbons long. We show that 1.5 mol % PEG-lipid represents a threshold concentration at which the chain length exerts a minimal effect on hepatic gene silencing but can still modify LNPs pharmacokinetics and biodistribution. Increasing the concentration to 2.5 and 3.5 mol % substantially compromises hepatocyte gene knockdown for PEG-lipids with distearyl (C18) chains but has little impact for shorter dimyristyl (C14) chains. These data are discussed with respect to RNA delivery and the different rates at which the steric barrier disassociates from LNPs in vivo.Molecular Therapy-Nucleic Acids (2013) 2, e139; doi:10.1038/mtna.2013.66; published online 17 December 2013.
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Mui
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Ying K
authors.initials: YK
authors.lastname: Tam
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Jayaraman
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Ansell
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Xinyao
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yuen Yi C
authors.initials: YY
authors.lastname: Tam
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Paulo Jc
authors.initials: PJ
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Chen
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Jayaprakash K
authors.initials: JK
authors.lastname: Narayanannair
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Maier
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Pieter
authors.initials: P
authors.lastname: Cullis
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Madden
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hope