Dual pH-responsive mesoporous silica nanoparticles for efficient combination of chemotherapy and photodynamic therapy

A kind of dual pH-responsive mesoporous silica nanoparticle (MSN)-based drug delivery system, which can respond to the cancer extracellular and intercellular pH stimuli, has been fabricated for synergistic chemo-photodynamic therapy. By grafting histidine onto the silica surface, the acid sensitive PEGylated tetraphenylporphyrin zinc (Zn-Por-CA-PEG) can be used as a gatekeeper to block the nanopores of MSNs by the metallo-supramolecular-coordinated interaction between Zn-Por and histidine. This gatekeeper is stable enough to prevent the loaded drug from leaching out in healthy tissue. However, at cancer extracellular pH (∼6.8) the conjugated acid sensitive cis-aconitic anhydride (CA) between Zn-Por and PEG will cleave and the surface of Zn-Por will be amino positively charged to facilitate cell internalization. Furthermore, the metallo-supramolecular-coordination will disassemble in intracellular acidic microenvironments (∼5.3) to release the carried drug and Zn-Por due to the removal of the gatekeeper. The photosensitivity of Zn-Por further makes it possible to combine chemotherapy and photodynamic therapy. This dual pH-sensitive MSN-based drug delivery system showed higher in vitro cytotoxicity than the single chemotherapy of free DOX or photodynamic therapy of Zn-Por, presenting its great potential for cancer treatment to overcome the challenges in efficient delivery in the site and ideal anti-cancer efficacy.