| RRC ID |
59907
|
| 著者 |
Sato Y, Hashiba K, Sasaki K, Maeki M, Tokeshi M, Harashima H.
|
| タイトル |
Understanding structure-activity relationships of pH-sensitive cationic lipids facilitates the rational identification of promising lipid nanoparticles for delivering siRNAs in vivo.
|
| ジャーナル |
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.
|
| 巻・号 |
295
|
| ページ |
140-152
|
| 公開日 |
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
|
| 引用数 |
17
|
| リソース情報 |
| ヒト・動物細胞 |
HeLa |
