Different kinetics for the hepatic uptake of lipid nanoparticles between the apolipoprotein E/low density lipoprotein receptor and the N-acetyl-d-galactosamine/asialoglycoprotein receptor pathway.

Journal of Controlled Release : Official Journal of the Controlled Release Society
Yusuke SatoHideyoshi Harashima

Abstract

Lipid nanoparticles (LNPs) are one of the more promising technologies for efficiently delivering nucleic acids in vivo. Hepatocytes are the primary target cells of LNPs that are delivered via the apolipoprotein E (ApoE)-low density lipoprotein receptor (LDLR) pathway, an endogenous targeting pathway. This robust targeting mechanism results in the specific and efficient delivery of nucleic acids to hepatocytes. Trivalent N-acetyl-D-galactosamine (GalNAc) is known to be a high-affinity exogenous ligand against the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes. In this study, we report that the kinetics of the hepatic uptake process between the two types of targeting pathways are different. Rapid blood clearance, accumulation to the space of Disse and a subsequent slow cellular uptake was observed in the case of the endogenous ApoE-LDLR pathway. On the other hand, both blood clearance and cellular uptake were more gradual in the case of the exogenous GalNAc-ASGPR pathway. Interactions between ApoE-bound LNPs and hepatic heparan sulfate proteoglycans (HSPGs) were involved in the rapid blood clearance and accumulation to the space of Disse in the case of the endogenous pathway. The findings presented ...Continue Reading

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Citations

Sep 17, 2020·Journal of Drug Targeting·Laura GauthierChristelle Gateau
Feb 27, 2021·Molecular Cancer·Lei MiaoLeaf Huang
Aug 14, 2020·Bioconjugate Chemistry·Valentina FranciaDominik Witzigmann
Sep 12, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Yuma YamadaHideyoshi Harashima
May 29, 2021·Acta Biomaterialia·Hanmei LiQiang Peng

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