Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo

Special (lipid) delivery: The role of the ionizable lipid pKa in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa value and silencing of the mouse FVII gene (FVII ED50) was f...

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Veröffentlicht in:	Angewandte Chemie International Edition 2012-08, Vol.51 (34), p.8529-8533
Hauptverfasser:	Jayaraman, Muthusamy, Ansell, Steven M., Mui, Barbara L., Tam, Ying K., Chen, Jianxin, Du, Xinyao, Butler, David, Eltepu, Laxman, Matsuda, Shigeo, Narayanannair, Jayaprakash K., Rajeev, Kallanthottathil G., Hafez, Ismail M., Akinc, Akin, Maier, Martin A., Tracy, Mark A., Cullis, Pieter R., Madden, Thomas D., Manoharan, Muthiah, Hope, Michael J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Amines - chemistry Animals Communications drug delivery Female Gene Silencing Genetic Therapy - methods Humans ionizable amino lipids Kinetics Lipids Lipids - administration & dosage Lipids - chemistry liposomes Liposomes - administration & dosage Liposomes - chemistry Liver - metabolism Liver - physiology Mice Mice, Inbred C57BL Nanoparticles Nanoparticles - administration & dosage Nanoparticles - chemistry Optimization Phospholipids RNA, Small Interfering - administration & dosage RNA, Small Interfering - chemistry RNA, Small Interfering - genetics siRNA
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Beschreibung
Zusammenfassung:	Special (lipid) delivery: The role of the ionizable lipid pKa in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa value and silencing of the mouse FVII gene (FVII ED50) was found, with an optimal pKa range of 6.2–6.5 (see graph). The most potent cationic lipid from this study has ED50 levels around 0.005 mg kg−1 in mice and less than 0.03 mg kg−1 in non‐human primates.
ISSN:	1433-7851 1521-3773
DOI:	10.1002/anie.201203263