Reference - Detail
| RRC ID | 59907 |
|---|---|
| Author | Sato Y, Hashiba K, Sasaki K, Maeki M, Tokeshi M, Harashima H. |
| Title | Understanding structure-activity relationships of pH-sensitive cationic lipids facilitates the rational identification of promising lipid nanoparticles for delivering siRNAs in vivo. |
| Journal | J Control Release |
| Abstract |
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. |
| Volume | 295 |
| Pages | 140-152 |
| Published | 2019-2-10 |
| DOI | 10.1016/j.jconrel.2019.01.001 |
| PII | S0168-3659(19)30001-X |
| PMID | 30610950 |
| MeSH | Animals Cations / chemistry Drug Carriers / chemistry HeLa Cells Humans Hydrogen-Ion Concentration Lipids / chemistry* Liver / metabolism Mice, Inbred BALB C Mice, Inbred ICR Nanoparticles / chemistry* RNA Interference* RNA, Small Interfering / administration & dosage* RNA, Small Interfering / genetics RNA, Small Interfering / pharmacokinetics Spleen / metabolism Structure-Activity Relationship |
| IF | 7.901 |
| Times Cited | 17 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 24 |
| Altmetric score changes over past 6months | 3.0 |
| Resource | |
| Human and Animal Cells | HeLa |