Super-pH-Sensitive Mesoporous Silica Nanoparticle-Based Drug Delivery System for Effective Combination Cancer Therapy

A multifunctional nanoplatform based on mesoporous silica nanoparticles (MSNs) was developed for combinational tumor therapy. Doxorubicin (DOX) was chosen as an antitumor drug and loaded into mesopores of MSNs via physical absorption. Then, a tumor-targeted fusion peptide conjugated with 2,3-dimethylmaleic anhydride (DTCPP) and a therapeutic peptide conjugated with 2,3-dimethylmaleic anhydride (DTPP) were introduced to the surface of MSNs as super-pH-sensitive nanovalves through disulfide linkages. The BSA adsorption assay confirmed the charge-reversal property of MSN-ss-DTPP&DTCPP nanoparticles at slightly acidic condition (pH 6.8) and superior stability in physiological environment (pH 7.4). According to the drug release research, both glutathione (GSH) and acidic condition are required for the accelerated drug release from DOX@MSN-ss-DTPP&DTCPP nanoparticles. Moreover, in vitro studies demonstrated the significantly reinforced tumor cellular uptake efficiency and mitochondrial disruption ability of DOX@MSN-ss-DTPP&DTCPP nanoparticles in tumor environment, in which DOX@MSN-ss-DTPP&DTCPP nanoparticles exhibited the preferred cytotoxicity toward α_vβ₃-positive human cervical carcinoma (HeLa) cells. We believe that the multifunctional dual-stimuli-sensitive MSN could provide an effective strategy for combinational tumor therapy.