*4.2. Redox-Responsive Gatekeepers*

Similar to the pH parameter, redox factor can also be exploited to achieve the controlled drug release from MSN specifically to the tumor environment. In general, glutathione (GSH) acts as a biological reducer and can cleave the redox-cleavable groups and trigger the bioactive agents. It has been observed that the GSH concentration in cancer cells is higher than that in normal cells [155]. Moreover, the intracellular concentration of GSH is in the range of 2–10 mM which is quite a bit higher than that in the extracellular part (2–20 nM); this concentration difference can allow the release of cargo from redox-responsive nanocarriers upon entering into the cytoplasm [156,157]. To take advantage of the high GSH concentration in cancer cells, the MSN surface has been decorated either with disulfide linkers or by incorporating any redox-cleavable group in capping moiety for the efficient release of cargo in cancer cells. As for an example, Kim et al. have used disulfide bonds as a linker in between MSN and the surface capping β-cyclodextrin moiety, and reported efficient doxorubicin toxicity in lung adenocarcinoma cells [158]. Moreover, Bräuchle and Bein research groups have reported cystein residues with disulfide linkers to modify the MSN surface [159]. Additionally, Wu et al. have used poly-(β-amino-esters) to seal the MSN pores and reported the intracellular reduction of disulfide linkers present between MSN and poly-(β-amino-esters) capping moiety [160]. The cargo release kinetics upon degradation of MSN can be further controlled by tuning the hindrance of disulfide or tetra-sulfide groups into the silica framework [161–163]. Besides, polymers cross-linked by cystamine, poly (propylene imine) dendrimer and polyethylenimine (PEI) via intermediate disulfide linkers are utilized to close the pores of MSN for a redox-responsive release of the chemotherapeutics by the degradation of polymeric networks in reducing the environment of the tumor site [164,165].
