Reduction-responsive drug delivery based on mesoporous silica nanoparticle core with crosslinked poly(acrylic acid) shell

Abstract

A novel reduction-responsive drug delivery system was successfully constructed with mesoporous silica nanoparticle (MSN) core as a drug carrier and poly(acrylic acid) (PAA) shell crosslinked by disulfide linkages as a drug release switcher. To keep the pore structure of MSN intact, PAA was covalently attached to the exterior surface of MSN before removing structure-template via radical polymerization. After removing structure-template and loading doxorubicin (DOX), the PAA shell was crosslinked by cystamine dihydrochloride through amidation reaction. The loading content and the entrapment efficiency of DOX could reach up to 40.2% and 80.4%, respectively. Because that the dissociation of disulfide linkage is reduction-responsive, the release behavior of DOX could be controlled by varying the concentration of reductant, and the release rate was 49.4% after 24h with the existence of 2mM glutathione (simulated environment of cancer cells), about three times higher than that of without glutathione (corresponding to normal human cells), which was only 16.9%. The in vitro cell assays demonstrated that the disulfide linkages crosslinked MSN–PAA (MSN–PAA-crosslinked) was highly biocompatible and suitable to use as drug carrier, and the DOX loaded MSN–PAA-crosslinked showed remarkable cytotoxicity to HeLa cells (human cancer cells), and relatively lower cytotoxicity to 293 cells (human normal cells). These results imply that the MSN–PAA-crosslinked is a promising platform to construct reduction-responsive controlled drug delivery system for cancer therapy.