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Published on: June 23, 2019
Pyrazolo[1,5-a]pyrimidine-Based Type-I Photosensitizer as an Efficient Pyroptosis Inducer for Tumor Ablation
Shuo Zhang1, Jingru Qiu1, Hao Zhang1
1Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China.
Abstract:
Pyroptosis is a proinflammatory and lytic programmed cell death form, which can promote cytotoxic T lymphocyte (CTL) maturation and tumor infiltration through the release of damage-associated molecular patterns (DAMPs). Therefore, the induction of pyroptosis by small molecules is a promising strategy to activate antitumor immunity. In this work, we report the design of a new class of pyrazolo[1,5-a]pyrimidine-based type-I photosensitizers (PSs) as efficient pyroptosis inducers for cancer photodynamic therapy (PDT). Among the compounds, ZS-3 exhibited the most excellent reactive oxygen species (ROS) generation ability and phototoxicity in vitro. It was found that ZS-3 induced cell pyroptosis through the caspase-3/gasdermin E (GSDME) pathway under light irradiation, characterized by bubble formation and damage-associated molecular pattern release. Furthermore, ZS-3 lipid nanoparticles significantly inhibited tumor growth and evoked antitumor immune responses in vivo.
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