Journal
JOURNAL OF CONTROLLED RELEASE
Volume 295, Issue -, Pages 140-152Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2019.01.001
Keywords
Structure-activity relationship; pH-sensitive cationic lipid; siRNA; Lipid nanoparticles; Delivery Endosomal escape; Hepatocytes
Funding
- Research Program on Hepatitis from Japanese Agency for Medical Research and Development (AMED) [PJ44280010]
- JSPS KAKENHI [JP15K20831, JP17H0505207]
- Ministry of Economy, Trade and Industry (MITI)
- JST CREST, Japan [JPMJCR17H1]
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Lipid nanoparticles (LNPs) are one of the more promising technologies for efficiently delivering short interfering RNA (siRNA) in vivo. A pH-sensitive cationic lipid that facilitates the targeting of hepatocytes and endosomal escape, strongly influences the availability of siRNA, thus making it a key material for efficient siRNA delivery. A systematic knowledge regarding lipid structure-activity relationships would greatly facilitate the development of sophisticated pH-sensitive cationic lipids for use in siRNA-based therapeutics. The systemic derivatization of a hydrophilic head group and hydrophobic tails of YSK12-C4, a pH-sensitive cationic lipid that was developed in our laboratory, revealed that hydrophilic head significantly affected the apparent pKa of the final product, a key factor in both intrahepatic distribution and endosomal escape. The clogP value of a hydrophilic head group was found to be associated with the apparent pKa of the product. In contrast, the hydrophobic tail structure strongly affected intrahepatic distribution without depending on apparent pKa. A structure-activity relationship study enabled the selection of an adequate combination of a hydrophilic head group and hydrophobic tails and permitted a potent LNP composed of a pH-sensitive cationic lipid CL4H6 (CL4H6-LNPs) to be developed that showed efficient gene silencing activity (50% effective dose: 0.0025 mg/kg), biodegradability and was tolerated. In vivo experiments revealed that the CL4H6-LNPs showed a superior efficiency for endosomal escape, cytosolic release and the RNA-induced silencing for the complex-loading of siRNAs compared to the previously developed LNPs.
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