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Mixing lipids to manipulate the ionization status of lipid nanoparticles for specific tissue targeting

Authors Shobaki N, Sato Y, Harashima H

Received 18 September 2018

Accepted for publication 27 October 2018

Published 10 December 2018 Volume 2018:13 Pages 8395—8410


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Thomas Webster

Nour Shobaki,* Yusuke Sato,* Hideyoshi Harashima

Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan

*These authors contributed equally to this work

Introduction: The development of targeted drug delivery systems is a rapidly growing area in the field of nanomedicine.
Methods: We report herein on optimizing the targeting efficiency of a lipid nanoparticle (LNP) by manipulating the acid dissociation constant (pKa) value of its membrane, which reflects its ionization status. Instead of changing the chemical structure of the lipids to achieve this, we used a mixture of two types of pH-sensitive cationic lipids that show different pKa values in a single LNP. We mixed various ratios of YSK05 and YSK12-C4 lipids, which have pKa values of 6.50 and 8.00, respectively, in one formulation (referred to as YSK05/12-LNP).
Results: The pKa of the YSK05/12-LNP was dependent not only on the molar ratio of each lipid but also on the individual contribution of each lipid to the final pKa (the YSK12-C4 lipid showed a higher contribution). Furthermore, we succeeded in targeting and delivering short interfering RNA to liver sinusoidal endothelial cells using one of the YSK05/12-LNPs which showed an optimum pKa value of 7.15 and an appropriate ionization status (~36% cationic charge) to permit the particles to be taken up by liver sinusoidal endothelial cells.
This strategy has the potential for preparing custom LNPs with endless varieties of structures and final pKa values, and would have poten­tial applications in drug delivery and ionic-based tissue targeting.

Keywords: acid dissociation constant, liver sinusoidal endothelial cells, physical targeting, short interfering RNA

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