Exploring glutathione-decorated micelles for drug delivery: A promise for enhanced cellular uptake

This study aimed to evaluate the effect of thiolated micelles on the cellular uptake of their payload. Reduced and oxidized glutathione were covalently attached to palmitic acid via amide bond formation. Micelles formed with these thiolated surfactants (M_P-GSH and M_P-GSSG-P) were evaluated regarding critical micellar concentration (CMC) and hemolytic activity. Cytotoxicity was evaluated on HEK 293 and HeLa cells. Diffusion of micelles in these cells was evaluated by fluorescence correlation spectroscopy (FCS). Furthermore, cellular uptake of micelles containing coumarin-6 as model drug was analyzed by flow cytometry and confocal laser scanning microscopy. CMC of M_P-GSSG-P, M_P-GSH, and palmitic acid micelles (M_PA) was determined to be 0.455 mM, 0.166 mM, and 0.046 mM, respectively. At a concentration of 0.5 % M_P-GSSG-P, M_P-GSH, and M_PA caused around 80 % hemolysis. In HEK cells, M_P-GSSG-P exhibited toxicity at a concentration of 0.25 %, while M_P-GSH showed toxicity at 0.06 % after 4 hours of incubation. In contrast, HeLa cells were more resilient, with only M_P-GSH showing toxicity at 0.25 %. Diffusivity of M_P-GSH and M_P-GSSG-P within the cells was higher than that of M_PA. Cellular uptake studies demonstrated a significantly (p < 0.05) enhanced internalization of M_P-GSH and M_P-GSSG-P, that was 112-fold and 270-fold higher in HEK 293 cells and 12-fold and 60-fold higher in HeLa cells when compared to M_PA. These findings suggest that M_P-GSH and M_P-GSSG-P could serve as promising vehicles for enhancing cellular uptake of drugs.