Disulfide crosslinked PEGylated starch micelles as efficient intracellular drug delivery platforms

Novel reduction-responsive disulfide core-crosslinked micelles based on amphiphilic starch-graft-poly(ethylene glycol) (starch-g-PEG) were prepared and used for efficient intracellular drug delivery. The starch-g-PEG copolymers can be conveniently prepared by grafting starch with carboxyl group terminated PEG, and subsequently conjugated with lipoic acid for disulfide crosslinking. The self-assembled starch-g-PEG micelles and the corresponding disulfide core-crosslinked micelles were then characterized by transmission electron microscopy, dynamic laser scattering and fluorescence techniques. It is interesting to observe that the hydrodynamic radii of disulfide core-crosslinked micelles would increase gradually in phosphate buffered saline (PBS) due to the cleavage of the disulfide bond in the micellar core, caused by the presence of reductive glutathione (GSH). The glutathione-responsive behaviors of the disulfide core-crosslinked micelles should be attractive for intracellular drug delivery. Thus, a model anticancer drug doxorubicin (DOX) was loaded into micelles and the in vitro drug release in response to GSH was also studied. The results showed that only a small amount of loaded DOX was released from the core-crosslinked starch-g-PEG micelles in PBS solution without GSH, while quick release occurred in the presence of 10.0 mM GSH. Confocal laser scanning microscopy and flow cytometry analyses further demonstrate that the disulfide crosslinked micelles exhibited a faster drug release behavior in glutathione monoester (GSH-OEt) pretreated HeLa cells than that in the nonpretreated and buthionine sulfoximine (BSO) pretreated cells. In addition, the DOX-loaded crosslinked micelles show higher cellular proliferation inhibition against GSH-OEt pretreated HeLa and HepG2 than against the nonpretreated and BSO pretreated ones. These results suggest that such disulfide crosslinked starch-g-PEG micelles, which can efficiently release the loading drug in response to intracellular GSH concentration, may provide favorable platforms for cancer therapy.