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.

Cyclodextrin‐Derived ROS‐Generating Nanomedicine with pH‐Modulated Degradability to Enhance Tumor Ferroptosis Therapy and Chemotherapy

“…Briefly, cells were seeded (5 × 10 3 cells per well) in 96-well plates and cultured for 24 h in a final volume of 100 µL. The cells were further incubated with blank DMEM or increasing concentrations of DHA (5,10,20,40,80,160,320, and 640 µm) for 24 h. MTT solution (20 µL, 5 mg mL −1 ) was added and incubated for another 4 h. After discarding the medium and 150 µL DMSO was added to each well. The absorbance was measured by a Versamax microplate reader at 495 nm.…”

“…[ 4 ] The generation of reactive oxygen species (ROS) is one of the main mechanisms for emerging anti‐cancer strategies. [ 5,6 ] Under physiological conditions, cells control the level of ROS by using the scavenging system to balance the ROS production and elimination. Excessive ROS can damage DNA, proteins, and lipids of cells, leading to cell damage.…”

Development of “smart” drug delivery systems for chemo/PDT synergistic treatment

“…Yu et al reported a versatile GSH-inhibiting nanosystem (PCNPs) for persistent synergistic therapy of cancer. 112 PCNPs not only demonstrated a prolonged release of buthionine sulfoximine to sustainably suppress the biosynthesis of GSH and improved drug utilization for efficient chemotherapy, but also acted as an efficient photo-induced singlet oxygen radical generator that prevents the loss of ROS, enhancing photodynamic therapy. Diselenide-rich polymers were developed for redox-responsive drug delivery as well.…”

Glutathione/Glucose-Depleting Nanoparticles with NO Generation for Ferroptosis/Starvation/NO-Induced Cancer Therapy

“…Glutathione (GSH), an intracellular tripeptide, has been considered a critical modulator for tumor initiation, progression, and metastasis. , Moreover, GSH is involved in the resistance to many therapeutic approaches, including reactive oxygen species (ROS)-based therapy, − immunotherapy, − and chemotherapy. − In light of this, consumption of intracellular GSH is recognized as a potent strategy to combat cancer. Another important role of GSH in cells is to maintain redox homeostasis.…”