Reduction-sensitive core-cross-linked mPEG–poly(ester-carbonate) micelles for glutathione-triggered intracellular drug release
作者:Lesan Yan
关键字:micelles
论文来源:期刊
发表时间:2012年
A functionalized six-membered cyclic carbonate monomer containing a protected thiol group, 2-(2,4-
dinitrophenylthio)ethyl-5-methyl-2-oxo-1,3-dioxane-5-carboxylate (MTC), was prepared. Ring-
opening polymerization (ROP) of MTC and L-lactide (LA) initiated by monohydroxyl poly(ethylene
glycol) (mPEG) was successfully performed with controlled polymer molecular weight and molecular
weight distribution. The structures of the obtained monomer and copolymers were con?rmed by NMR
and FTIR. After deprotection under mild conditions, the amphiphilic block copolymer was self-
assembled into micelles in aqueous solution. By oxidation of the free thiol groups in the PMTC
segments, the micelles with the cross-linked core were formed, and the enhanced stability against
disruptive conditions was demonstrated by dynamic light scattering (DLS) measurement in the
presence of DMF. Doxorubicin (DOX) was loaded into the micelles as a model drug. The in vitro DOX
release behaviors indicated that cross-linking of the micelle cores resulted in a slow drug release and this
process was greatly accelerated by adding glutathione (GSH) solution with comparable concentrations
to intracellular levels in tumor cells. The cross-linked micelles were demonstrated to be ef?ciently
internalized into the cells. Faster intracellular DOX release was observed by confocal laser scanning
microscopy (CLSM) in the GSH pretreated MCF-7 cells than in the unpretreated MCF-7 cells. In vitro
MTT assay revealed that the cross-linked micelles were biocompatible with L929 cells and MCF-7 cells.
As expected, DOX-loaded cross-linked micelles showed higher cellular proliferation inhibition towards
glutathione pretreated MCF-7 cells than that towards the unpretreated ones at various GSH
concentrations. These results indicated that the bioreducible core-cross-linked micelles can be used as
drug carriers for intelligent drug delivery.