An in situ self-assembled peptide derivative for inhibition of glutathione synthesis and selective enhancement of tumor radiotherapy

Background: Inhibition of glutathione (GSH) synthesis in cancer cells considerably improves the efficacy of reactive oxygen species (ROS)-related tumor therapy. Self-assembled peptide derivatives can facilitate the efficient delivery and accumulation of small molecular drugs in cancer cells. Methods: Self-assembling modules were covalently linked to the GSH-biosynthesis inhibitor l-buthionine sulfoximine (BSO) by solid-phase synthesis to form the self-assembling peptide derivative Nap-^DF^DFpY-GG-BSO (Nano-BSO^{@ in situ}). Subsequently, its enzyme-instructed self-assembly in vitro and on cell surfaces were confirmed, and its intracellular GSH depletion and radiotherapy-sensitizing effects were determined. Results: Nano-BSO^{@ in situ} successfully self-assembles into a hydrogel with a nanofibrous microstructure upon incubation with alkaline phosphatase (ALP) at a critical concentration of 9.84 μM. Furthermore, it selectively self-assembles in situ on HeLa cells with high ALP expression. At a concentration of 50 μM, Nano-BSO^{@ in situ} decreases intracellular GSH levels by 80%, ∼2.3 times more than free BSO. Meanwhile, pretreatment of HeLa cells with 50 μM Nano-BSO^{@ in situ} for 24 h results in a radiotherapy sensitization enhancement ratio to γ-rays of 2.09. Conclusions: A novel in situ self-assembling peptide derivative for GSH depletion and selective enhancement of tumor radiotherapy was constructed. The excellent GSH-depletion ability and remarkable radiotherapy-enhancement performance indicate that Nano-BSO^{@ in situ} is a promising selective sensitizer for ROS-related treatment of tumor cells with high ALP expression.