A Potent Strategy of Combinational Blow Toward Enhanced Cancer Chemo-Photodynamic Therapy via Sustainable GSH Elimination.

ABSTRACT

Excessive glutathione (GSH), which is produced owing to abnormal metabolism of tumor cells, scavenges photo-induced reactive oxygen species (ROS) and consumes chemotherapeutic drugs, thereby attenuating the efficacy of photodynamic therapy and chemotherapy, respectively. Predominant strategies for GSH inhibition involve its chemical depletion, which only leads to a temporary therapeutic effect because GSH is replenished via various compensatory routes in tumor cells. Here, a versatile GSH-inhibiting nanosystem (termed PCNPs) for persistent synergistic therapy of cancer is reported. The porous skeleton of PCNPs allows easy encapsulation of buthionine sulfoximine (BSO) to sustainably suppress the biosynthesis of GSH. Thus, PCNPs not only demonstrate a prolonged release of BSO and improve drug utilization for efficient chemotherapy, but also act as an efficient photo-induced singlet oxygen radical generator that prevents the loss of ROS, thereby enhancing photodynamic therapy. In addition, the liposomal coating prevents cargo release in the blood, improves the accumulation of PCNPs at the tumor site, and promotes the cellular uptake of oxaliplatin and BSO. This strategy is applicable to ROS-based therapy and chemotherapy, which are suppressed by GSH, and may further enhance the synergistic effect of GSH-restrained therapy.