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

By M. Jayaraman, S. Ansell, B. Mui, Ying K. Tam, Jianxin Chen, Xinyao Du, David Butler, Laxman Eltepu, S. Matsuda, Jayaprakash K. Narayanannair and 9 more. Angewandte Chemie, 2012

1,185 citations recorded by the source corpus.

Special (lipid) delivery: The role of the ionizable lipid pK(a) 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 pK(a) value and silencing of the mouse FVII gene (FVII ED(50) ) was found, with an optimal pK(a) range of 6.2-6.5. The most potent cationic lipid from this study has ED(50) levels around 0.005 mg kg(-1) in mice and less than 0.03 mg kg(-1) in non-human primates.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e3504af52d1016a578875200a5d527d3ccd1739f

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Citations in the corpus

• Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines (2019, methodology): “8.(11,13,23) However, the best lipids with respect to protein expression after IV administration generally had lower pKas than the best lipids for protein expression after IM administration.”
• The role of lipid components in lipid nanoparticles for vaccines and gene therapy (2022, neutral): “3 of 56 ionizable lipids consisting of a dilinoleyl-based hydrophobic tail with varying headgroups [10].”
• The delivery of therapeutic oligonucleotides (2016, background): “Two important steps for optimizing the cationic lipids were (i) altering the pKa so that the lipids were almost uncharged in the circulation but became charged in the low pH endosome and (ii) using linkages that were readily biodegradable (172,173).”
• Liposomal drug delivery systems: from concept to clinical applications. (2013, methodology): “The new LNP siRNA made with “next generation” ionizable cationic lipids showed very good in vivo knockdown in rodent liver using the Factor VII assay [209,213] at dose levels as low as 0.”