*4.1. PH-Responsive Gatekeepers*

One of the most promising internal stimuli that has been employed for controlled drug release in cancer therapy is to exploit the lower pH values in most of the tumors in comparison with healthy tissues [136]. Actually, in cancer cells, because of high glycolysis rate, the production of lactic acid is high, thus eventually reducing the pH value in the tumor region. There are various reports in the literature regarding the pH-controlled delivery of chemotherapeutics by surface-engineered MSN in cancer therapy. Besides, there are mainly two ways in which they have been used to decorate the MSN for exploiting the pH sensitivity of tumor cells. One approach is to incorporate the pH responsive linkers in between MSN and the capping moiety usually used for blocking the pore entrances of MSN. There are several linkers that have been reported for the intracellular pH-responsive controlled delivery of anti-cancer drugs e.g., acetal linkers [137], boronate ester linkers [138], ferrocenyl linkers [139], aromatic amines [140], imine bonds [141] hydrazine linkers [142], acid labile amide bond [143], etc.

Another widely used approach is to modify the MSN surface with pH sensitive capping moiety, so that the MSN will only open up at acidic pH, release the cargo only in tumor environment and

avoid any premature release of drugs on healthy tissues [144,145]. Yang and co-workers have reported that the MSN coated with pH-responsive chitosan/polymethacrylic acid polymer is more efficient to deliver doxorubicin in HeLa cells compared to the uncoated MSN [146]. The modification of the MSN surface using pH-sensitive self-immolative polymers, poly(acrylic acid), nanovalves, such as pseudorotaxane encircled by β-cyclodextrin, tannic acid, lipid coatings and many other nanoparticles have been reported [147–150]. Zhu and coworkers have used a pH-sensitive nanovector for the dissolution of ZnO nanoparticles functionalized onto the surface of MSN for the efficient delivery of doxorubicin in HeLa cells [151]. Moreover, pH degradable calcium phosphate coated MSN and gelatin capped MSN have also been described for intracellular acid-triggered drug delivery [152,153]. In a recent report, the MSN surface was modified with poly (styrene sulfonate) (PSS), which can act as a "nano-gate" for the pH responsive controlled release of curcumin [154].
