Engineered chemoswitchable mesoporous silica for tumor-specific cytotoxicity

Abstract

Specific release of drugs in the tumor microenvironment can significantly enhance the therapeutic efficiency. This work attempts to develop a mesoporous silica carrier that can selectively release drugs in the tumor microenvironment. Mesoporous silica nanoparticles (MCM-41) with spherical morphology were synthesized using the sol–gel method. The MCM-41 nanoparticles were then functionalized with 3-mercaptopropyltrimethoxysiliane (MPTMS), an organic thiol linker, through evaporation-induced self-assembly. Both unmodified and thiol-functionalized nanoparticles were characterized using electron microscopy, spectroscopy, thermogravimetry and surface area analysis. The mesoporous architecture of MCM-41 was used to load 5-fluorouracil (5-FU). The thiol functionalization enabled easy oxidation of the sulphydryl groups and formed disulphide cross-links, which was found to retard the drug release when compared to unmodified MCM-41. Addition of the reduced form of glutathione to the thiol-functionalized system was found to enhance the drug release through lysis of the disulphide links by reduction. The correlation between the amount of drug released and the disulphide cross-links was established by addition of reduced glutathione at alternate time points where a step-wise release profile was observed, thereby establishing the chemosensitivity of the thiol-functionalized MCM-41. Cell culture studies revealed that the cancer cells were more susceptible to the thiol-functionalized 5-FU loaded MCM-41 when compared with normal cells. The mechanism involves both membrane perturbation as well as high intracellular glutathione levels. These results indicate that this chemoswitchable system might be effective against cancer cells as they contain large amounts of reduced glutathione, demonstrating the potential of this carrier as a next generation ‘smart’ delivery system.