Sequential Drug Release by pH/Redox Dual Responsive Non-covalent Polymer Gatekeepers in Hollow Mesoporous Silica Nanoparticle for synergistic cancer therapy

Nanoscopic delivery vehicles capable of encapsulating drug molecules and releasing them in response to external stimuli are of great interest due to implications in therapeutic applications. Sequential drug delivery with dual stimulus responsive nanotherapeutics is highly desirable for disease specific treatment in cancer therapy with minimized adverse effects. In addition to this, on-demand therapy received considerable attention among the treatment techniques. Herein, we present the design of robust, new and simple pH dependent charge conversional non-covalent polymer gatekeepers technique by preparing the hydrophilic and hydrophobic drug loading at high capacity and improved encapsulation stability in hollow mesoporous container for target specific cellular uptake for cancer treatment. The di-isopropyl methacrylate functionalized monomer facilitates the fast cellular uptake at acidic environment of cancer cells and allows the on-demand release of hydrophillic drug at acidic pH of endosomes upon protonation. Pyridine disulfide facilitates the strong encapsulation of loaded cargo upon crosslinking by thiol-disulfide exchange and releases the cargo upon exposure with increased intracellular glutathione concentration. The co-delivery of the multi-drugs in single carrier enables a synergistic chemotherapeutic effect. Based on this new design, a wide range of sequential and synergistic therapy can be achieved to satisfy varied clinical requirements