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 Cu2-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.