Co-delivery of doxorubicin and glycyrrhetinic acid via acid/glutathione dual responsive nano-prodrug with sodium bicarbonate carry-on for advanced combinational cancer treatment

The combination of doxorubicin (Dox) and glycyrrhetinic acid (GA) has been widely explored for treating various cancers, while the heterogeneous distribution, uncontrolled release and acid tumor microenvironment often hinder their synergistic effects. Herein, we introduce an acid/glutathione (GSH)-dual responsive nano-prodrug (AS1411@Dox + GA/NPs) enabling precise co-delivery of Dox and GA for enhanced combination therapy. The GSH-activated Dox prodrug [Poly(lactic- co -glycolic acid)-disulfide-Dox, PLGA-ss-Dox], GA, and sulfur-terminated D-α-tocopherol polyethylene glycol succinate (TPGS-SH) are combined to form a nanoemulsion with sodium bicarbonate (NaHCO 3 ) in the aqueous phase. The AS1411 aptamer is modified on the surface for tumor-specific targeting. Upon reaching the tumor via enhanced penetration and retention effects, AS1411 aptamer medicates specific endocytosis of AS1411@Dox + GA/NPs into tumor cells. Intracellularly, the acidic endosomal environment promotes carbon dioxide (CO 2 ) production from NaHCO 3 , disrupting the nanoemulsion and causing a burst release of GA and PLGA-ss-Dox prodrug. Concurrently, high levels of GSH in the cytoplasm triggers the cleavage of the disulfide linker, thereby releasing Dox. Notably, the released NaHCO 3 consumed hydrogen ion (H + ), amplifying the sensitivity of tumor cells to Dox. As a consequence, AS1411@Dox + GA/NPs exhibits remarkable synergistic therapeutic efficacy on both liver cancer and breast cancer bearing mouse models. This work presents an appealing approach utilizing stimuli-sensitive nano-prodrug for advanced combinational cancer treatment.