Boosting the therapy of glutamine-addiction glioblastoma by combining glutamine metabolism therapy with photo-enhanced chemodynamic therapy

Abstract

The complete treatment of high grade invasive glioblastoma (GBM) remains to be a great challenge, and it is of great importance to develop innovative therapeutic approaches. Herein, we found that GBM derived from U87 MG cells is a glutamine-addiction tumor, and jointly using glutamine-starvation therapy and photo-enhanced chemodynamic therapy (CDT) can significantly boost its therapy. We rationally fabricated tumor cell membrane coated Cu_2−xSe nanoparticles (CS NPs) and an inhibitor of glutamine metabolism (Purpurin) for combined therapy, because glutamine rather than glucose plays a crucial role in the proliferation and growth of GBM cells, and serves as a precursor for the synthesis of glutathione (GSH). The resultant CS–P@CM NPs can be specifically delivered to the tumor site to inhibit glutamine metabolism in tumor cells, suppress tumor intracellular GSH, and increase H₂O₂ content, which benefit the CDT catalyzed by CS NPs. The cascade reaction can be further enhanced by irradiation with the second near-infrared (NIR-II) light at the maximum concentration of H₂O₂, which can be monitored by photoacoustic imaging. The NIR-II light irradiation can generate a large amount of reactive oxygen species (ROS) within a short time to kill tumor cells and enhance the CDT efficacy. This is the first work on the treatment of orthotopic malignant GBM through combined glutamine metabolism therapy and photo-enhanced CDT, and provides insights into the treatment of other solid tumors by modulating the metabolism of tumor cells.