Lowering glutathione level by buthionine sulfoximine enhances in vivo photodynamic therapy using chlorin e6-loaded nanoparticles

Abstract

Synergetic effects in mechanisms are important for successful combination therapy. Herein, we used buthionine sulfoximine (BSO) to reduce the cytosolic concentration of glutathione (GSH), a natural scavenger of reactive oxygen species (ROS). We then performed photodynamic therapy (PDT) using chlorin e6-loaded poly(ethylene glycol)-block-poly(D,L lactide) nanoparticles (Ce6-PEG-PLA-NPs). Upon laser irradiation, cytotoxic ROS generated from Ce6-PEG-PLA-NPs killed tumor cells effectively due to the reduced concentration of GSH with addition of BSO. When intravenously injected into tumor-bearing mice, Ce6-PEG-PLA-NPs resulted in efficient delivery of Ce6 to tumor tissues, as shown in near-infrared fluorescence (NIRF) imaging. The accumulation of Ce6 in tumor tissue was more than 2 folds increased by Ce6-PEG-PLA-NPs at every time points. The synergetic effect of reduced GSH synthesis by BSO and efficient delivery of Ce6-PEG-PLA-NPs to tumor tissue was observed in a mouse model after laser irradiation. The combination of BSO and Ce6-PEG-PLA-NPs resulted in complete suppression of tumor, while BSO or Ce6-PEG-PLA-NPs-treated tumors grew to about 1800 and 400 mm3, respectively. The overall results suggest that the combination of BSO and photosensitizer-loaded NPs is effective and demonstrates promise for tumor therapy.