Glutathione-Responsive Polymersome with Continuous Glutathione Depletion for Enhanced Photodynamic Therapy and Hypoxia-Activated Chemotherapy

The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-...

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Published in:ACS macro letters 2024-05, Vol.13 (5), p.599-606
Main Authors: Cheng, Guohui, Tao, Shuang, Liu, Shuang, Wang, Ping, Zhang, Chi, Liu, Jin, Hao, Chuanchuan, Wang, Sheng, Guo, Dong, Xu, Bo
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Chlorophyllides
Glutathione - metabolism
Humans
Mice
Photochemotherapy - methods
Photosensitizing Agents - pharmacology
Photosensitizing Agents - therapeutic use
Porphyrins - administration & dosage
Porphyrins - pharmacokinetics
Porphyrins - pharmacology
Prodrugs - pharmacology
Tirapazamine - pharmacology
Tumor Microenvironment - drug effects
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Summary:The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.
ISSN:2161-1653
2161-1653
DOI:10.1021/acsmacrolett.4c00125