In-depth study of anticancer drug diffusion through a cross-linked ­pH-responsive polymeric vesicle membrane

Post-encapsulation and release of the anticancer drug doxorubicin hydrochloride (DOX·HCl) through cell-like transmission functions of polymeric vesicles were studied using cross-linked pH-responsive polymeric vesicles. The vesicles were fabricated for the first time via the redox-initiated reversible addition-fragmentation chain transfer dispersion polymerization in ethanol-water mixture, using 2-(diisopropylamino)ethyl methacrylate and glycidyl methacrylate, and the vesicle membrane was modified post-cross-linking by using ethylenediamine. A phase diagram was constructed for reproducible fabrication of the polymeric vesicles, and well-shaped vesicles were formed when the target degree of polymerization of the hydrophobic polymer chains was equal to or higher than 50 with solid content in the range of 10–30 wt%. The cross-linked vesicle membrane served as a gate enabling “open” and “closed” states in response to pH stimulation. Up to 50% drug loading efficiency and 39% drug loading content could be achieved, and in vitro release of the DOX-loaded vesicles in aqueous buffer solutions showed a much faster DOX release rate at pH 5.0 than at pH 6.5. The polymeric vesicles were of very low cytotoxicity to A549 cells up to the concentration of 2 mg/mL, and the IC(50) of DOX-loaded vesicles were higher than that of the free DOX. The intracellular DOX release study indicated higher cellular uptake capability for DOX-loaded vesicles than that of free DOX.