title: Influence of particle size on the in vivo potency of lipid nanoparticle formulations of siRNA.
abstract: Lipid nanoparticles (LNP) can provide a clinically effective method for delivering small interfering RNA (siRNA) to silence pathological genes in hepatocytes. The gene silencing potency of these LNP-siRNA systems has been shown to depend on a variety of factors including association with serum factors such as ApoE and the pKa of component ionizable lipids. Here we investigate the influence of LNP size, an important parameter affecting tissue penetration of LNP systems, on the pharmacokinetics, biodistribution, and hepatic gene silencing potency of LNP-siRNA systems following intravenous administration. For LNP systems stabilized by a polyethylene glycol (PEG)-lipid that can dissociate from the LNP following injection, it is shown that small (diameter≤30nm) systems are considerably less potent than their larger counterparts. This is attributed in part to the ability of other lipid components, particularly the ionizable amino-lipid, to dissociate from the LNP following dissociation of the PEG-lipid. Small LNP stabilized by PEG-lipids with slow dissociation rates exhibited much reduced amino-lipid dissociation rates, however such systems are relatively impotent due to the continued presence of the PEG coating. These results demonstrate the delicate balance between the in vivo potency of LNP-siRNA systems and the residence times of component lipids in the LNP particle itself and suggest new directions to optimize the in vivo gene silencing potency of small LNP-siRNA systems.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Yuen Yi C
authors.initials: YYC
authors.lastname: Tam
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Acuitas Therapeutics, 2714 West 31st Avenue, Vancouver, British Columbia V6L 2A1, Canada.
authors.forename: Paulo J C
authors.initials: PJC
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Molly M H
authors.initials: MMH
authors.lastname: Sung
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Acuitas Therapeutics, 2714 West 31st Avenue, Vancouver, British Columbia V6L 2A1, Canada.
authors.forename: Ying K
authors.initials: YK
authors.lastname: Tam
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: pieterc@mail.ubc.ca.
authors.forename: Pieter R
authors.initials: PR
authors.lastname: Cullis
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D005167:Factor VII / Q000235:genetics / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D008055:Lipids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*; D010316:Particle Size; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D005167:Factor VII
keywords: Drug delivery; Lipid exchange; Lipid nanoparticles; Liposomes; Nanomedicine; siRNA