The valency of fatty acid conjugates impacts siRNA pharmacokinetics, distribution, and efficacy in vivo.

ABSTRACT: Lipid-conjugated small-interfering RNAs (siRNAs) exhibit accumulation and gene silencing in extrahepatic tissues, providing an opportunity to expand therapeutic siRNA utility beyond the liver. Chemically engineering lipids may further improve siRNA delivery and efficacy, but the relationship between lipid structure/configuration and siRNA pharmacodynamics is unclear. Here, we synthesized a panel of mono-, di-, and tri-meric fatty acid-conjugated siRNAs to systematically evaluate the impact of fatty acid structure and valency on siRNA clearance, distribution, and efficacy. Fatty acid valency significantly altered the physicochemical properties of conjugated siRNAs, including hydrophobicity and micelle formation, which affected distribution. Trivalent lipid-conjugated siRNAs were predominant

SUBMITTER: Biscans A 

PROVIDER: S-EPMC6546539 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature