Novel, Self-Distinguished, Dual Stimulus-Responsive Therapeutic Nanoplatform for Intracellular On-Demand Drug Release

On-demand drug release nanoplatforms are promising alternative strategies for enhancing the therapeutic effect of cancer chemotherapy. However, these nanoplatforms still have many drawbacks including rapid blood clearance, nontargeted specificity, and a lack of immune escape function. Even worse, they are also hindered via the dosage-limiting toxicity of traditional chemotherapeutic drugs. Herein, both dual-functional mannose (enhances the antitumor activity of chemotherapeutic drugs and exhibits an innate affinity against the lectin receptor) and amphiphilic d-α-tocopheryl polyethylene glycol 1000 succinate were selected to be covalently linked via a redox-responsive monothioether linkage. The synthesized self-distinguished polymer (TSM), as a structural motif, can be self-assembled into nanoparticles (TSM NPs) in an aqueous solution, in which doxorubicin (DOX) is loaded by weak interactions (TSM–DOX NPs). These TSM–DOX NPs can provide targeted, on-demand drug release under dual stimuli from lysosomal acidity and glutathione (GSH). In addition, TSM–DOX NPs can be self-distinguished via tumor cells in vitro and specifically self-distinguished from the tumor site in vivo. Further in vitro and in vivo research consistently demonstrated that TSM–DOX NPs display highly synergistic chemotherapeutic effects. Taken together, the data show that the self-distinguished GSH-responsive polymer TSM has the potential to load various therapeutic agents.