Redox and pH Responsive Switched Drug Release from Noncovalent Polymer Gatekeeper In Hollow Mesoporous Silica Nanoparticles for Sequential Therapy

Abstract

Multi-stage aspects of cancer treatment require sequential administration of chemodrugs for better efficacy. Multidrug resistance has long been considered as one criterion in failure of tumor therapy. Herein, we report a sequential combination drug delivery strategy exploiting pH-triggerable and redox switch to release cargos from the hollow silica nanoparticles in a spatiotemporal manner and overcome the drug resistance in tumor treatment. This smart system enables the large loading capacity for both hydrophobic and hydrophilic drugs inside the nanoparticles followed by self-crosslinking with disulfide and di-isopropyl methacrylate (DPA) functionalized polymers. The charge generation by DPA moiety facilitated the sequential release of hydrophillic drug veramphamil upon the acidic endosomal pH by swollen effect and intracellular glutathione concentraton regulated the release of hydrophobic doxorubicin upon the disintegration of polymer shell in a sequential manner. This is the one simple and robust system, which facilitates the endosomal and/or lysosomal escape and synergistic chemotherapeutic effect. The newly designed mesoporous silica nanoparticles can be applied for a wide range of sequential and synergistic therapy.