Targeted Photoredox System under a Hypoxic Environment to Evoke Photodynamic Immunotherapy.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-03 DOI:10.1021/acs.jmedchem.5c01579

Na Xu,Hongbao Fang,Zhirong Zhu,Yan Su,Zhi Su

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引用次数: 0

Abstract

Conventional oxygen dependent type-II photodynamic therapy (PDT) was significantly constrained by the hypoxic tumor microenvironment. Type-I photosensitizers (PSs) produce oxygen radicals through the electron transfer (ET) pathway and are less oxygen dependent. However, no proven design strategy for generic Type-I PSs has been clarified. In this work, type-I PS BDP-Ir-bpt has been successfully synthesized, with the modification of triplet state energy via ligand upgradation. Under hypoxia with 630 nm irradiation with PS BDP-Ir-bpt, the intracellular photoredox system was disrupted and intracellular O2-• and •OH were significantly produced. Oxygen radicals further ruptured the lysosomal membrane, releasing cathepsin B and inducing GSDMD-mediated pyroptosis. Subsequently, the innate immune responses were evoked, as observed in an in vivo mouse prophylactic model. This work not only provided a biocompatible photosensitizer to relieve the hypoxic microenvironment and initiate photodynamic immunotherapy but also demonstrated the importance of the rational structural design for cancer therapy.

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低氧环境下靶向光氧化还原系统引发光动力免疫治疗。

传统的氧依赖型ii型光动力治疗（PDT）明显受到低氧肿瘤微环境的限制。i型光敏剂（ps）通过电子转移（ET）途径产生氧自由基，对氧的依赖性较小。然而，通用i型ps的设计策略还没有得到证实。本文成功合成了i型PS BDP-Ir-bpt，并通过配体升级对三重态能进行了修饰。在630 nm低氧PS BDP-Ir-bpt照射下，细胞内光氧化还原系统被破坏，细胞内大量产生O2-•和•OH。氧自由基进一步破坏溶酶体膜，释放组织蛋白酶B，诱导gsdmd介导的热亡。随后，在体内小鼠预防模型中观察到，先天免疫反应被唤起。这项工作不仅提供了一种生物相容性光敏剂来缓解缺氧微环境和光动力免疫治疗，而且还证明了合理的结构设计对癌症治疗的重要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.