Self-assembled -tocopherol succinate dimer nanoparticles combining doxorubicin for increasing chemotherapy/oxidative therapy in 3D tumor spheroids

Mono-chemotherapy is inefficient and easily cause drug-resistance in clinical cancer treatment. In this work, a borate ester linked a-tocopherol succinate (a-TOS) dimer was developed and self-assembled with doxorubicin (DOX) to obtain hybrid nanodrugs (2BOH-TOS/DOX) to improve the deficiency of mono-chemotherapy. Hybrid nanodrugs were highly sensitive to H2O2 and triggered quickly DOX release via H2O2 stimulation. In vitro tests verified that hybrid nanodrugs could increase intracellular DOX levels through inhibiting ATP-dependent drugs efflux, resulting in higher cell-killing in drug-resistant tumor cells. In addition, nanodrugs could amplify oxidative therapy by inducing reactive oxygen species (ROS) generation and depleting intracellular glutathione (GSH). Furthermore, 3D cells experiments revealed that nanodrugs could effectively accumulate and penetrate in sensitive/resistant tumor-like spheroids, achieving higher antitumor effect through the combination of chemo/ oxidative therapy. Overall, this H2O2-sensitive nanodrugs was effective in reversing drug-resistance and synergistically treating tumors.