RRC ID 11936
Author Oba M, Miyata K, Osada K, Christie RJ, Sanjoh M, Li W, Fukushima S, Ishii T, Kano MR, Nishiyama N, Koyama H, Kataoka K.
Title Polyplex micelles prepared from ω-cholesteryl PEG-polycation block copolymers for systemic gene delivery.
Journal Biomaterials
Abstract Polyplex micelles formed with plasmid DNA (pDNA) and poly(ethylene glycol) (PEG)-block-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of diamine side chains with decreasing pH, which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer. Here, PEG-PAsp(DET) polyplex micelles were further improved as in vivo systemic vectors by introduction of cholesterol (Chole) into the ω-terminus of PEG-PAsp(DET) to obtain PEG-PAsp(DET)-Chole. Introduction of the cholesterol resulted in enhanced association of block copolymers with pDNA, which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to PEG-PAsp(DET) micelles. The synergistic effect between enhanced polymer association with pDNA and increased micelle stability of PEG-PAsp(DET)-Chole polyplex micelles led to high in vitro gene transfer even at relatively low concentrations, due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA. Finally, PEG-PAsp(DET)-Chole micelles achieved significant suppression of tumor growth following intravenous injection into mice bearing a subcutaneous pancreatic tumor using therapeutic pDNA encoding an anti-angiogenic protein. These results suggest that PEG-PAsp(DET)-Chole micelles can be effective systemic gene vectors for treatment of solid tumors.
Volume 32(2)
Pages 652-63
Published 2011-1-1
DOI 10.1016/j.biomaterials.2010.09.022
PII S0142-9612(10)01175-0
PMID 20932567
MeSH Animals Cell Line, Tumor Female Gene Transfer Techniques* Humans Mice Mice, Inbred BALB C Mice, Nude Micelles* Microscopy, Confocal Microscopy, Fluorescence Polyamines / chemistry* Polyethylene Glycols / chemistry* Polymers / chemistry* Serum Albumin, Bovine / chemistry Transfection / methods Ultracentrifugation
IF 10.273
Times Cited 78
DNA material pCAcc-Luc+ (RDB02443)