Smart polyion complex micelles for targeted intracellular delivery of PEGylated antisense oligonucleotides containing acid-labile linkages

Motoi Oishi, Fumi Nagatsugi, Shigeki Sasaki, Yukio Nagasaki, Kazunori Kataoka

研究成果: Contribution to journalArticle査読

101 被引用数 (Scopus)

抄録

A novel pH-sensitive and targetable antisense ODN delivery system based on multimolecular assembly into polyion complex (PIC) micelles of poly(L-lysine) (PLL) and a lactosylated poly(ethylene glycol)-antisense ODN conjugate (Lac-PEG-ODN) containing an acid-labile linkage (β-propionate) between the PEG and ODN segments has been developed. The PIC micelles thus prepared had clustered lactose moieties on their peripheries and achieved a significant antisense effect against luciferase gene expression in HuH-7 cells (hepatoma cells), far more efficiently than that produced by the nonmicelle systems (ODN and Lac-PEG-ODN) alone, as well as by the lactose-free PIC micelle. In line with this pronounced antisense effect, the lactosylated PIC micelles showed better uptake than the lactose-free PIC micelles into HuH-7 cells; this suggested the involvement of an asialoglycoprotein (ASGP) receptor-mediated endocytosis process. Furthermore, a significant decrease in the antisense effect (27% inhibition) was observed for a lactosylated PIC micelle without an acid-labile linkage (thiomaleimide linkage); this suggested the release of the active (free) antisense ODN molecules into the cellular interior in response to the pH decrease in the endosomal compartment is a key process in the antisense effect. Use of branched poly(ethylenimine) (B-PEI) instead of the PLL for PIC micellization led to a substantial decrease in the antisense effect, probably due to the buffer effect of the B-PEI in the endosome compartment, preventing the cleavage of the acid-labile linkage in the conjugate. The approach reported here is expected to be useful for the construction of smart intracellular delivery systems for antisense ODNs with therapeutic value.

本文言語英語
ページ(範囲)718-725
ページ数8
ジャーナルChemBioChem
6
4
DOI
出版ステータス出版済み - 4 1 2005

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子医療
  • 分子生物学
  • 有機化学

フィンガープリント

「Smart polyion complex micelles for targeted intracellular delivery of PEGylated antisense oligonucleotides containing acid-labile linkages」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル