Non-linear pharmacokinetics of octaarginine-modified lipid nanoparticles: barriers from in vitro to in vivo.
A rational development of an efficient siRNA delivery system is important for streamlining the RNAi-based drug development process. However, a huge gap frequently exists between in vitro and in vivo activity, which is the rate-limiting step for developing versatile nanoparticles. We report herein on a remarkable non-linearity in pharmacokinetics (PK), but not pharmacodynamics (PD) using octaarginine (R8) modified lipid nanoparticles in mice. A quantitative study of siRNA molecules between cultured cells and mouse liver revealed a high correlation between intracellular siRNA molecules and their RNAi activities, indicating that there was no significant difference in the efficiency in PD. In contrast, a remarkable difference was observed in the non-linearity in PK. Quantitative analysis of the time profile for siRNA showed that the percentage of siRNA accumulation in mice was severely decreased with decreasing input dose compared to in vitro data. These unexpected data reveal an important clue to bridging the gap between in vitro and in vivo activity.
Laboratory of Innovative Nanomedicine, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.
Yasuhiro
Y
Hayashi
Yuki
Y
Noguchi
Hideyoshi
H
Harashima
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D020868:Gene Silencing; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013228:Stearates / Q000008:administration & dosage* / Q000493:pharmacokinetics
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D009842:Oligopeptides; D010714:Phosphatidylethanolamines; D034741:RNA, Small Interfering; D013228:Stearates; C487882:stearyl-octaarginine