Li Zhenzhen, Liu Qiaolin, Wang Guorong, Bai Ru, Li Shengmin, Liu Tao, Wang Qingzhen, Peng Yufeng, Teng Fei, Zhou Huige, Xian Junfang, Chen Chunying
Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, P.R. China.
New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, P.R. China.
Angew Chem Int Ed Engl. 2025 Jul;64(29):e202421481. doi: 10.1002/anie.202421481. Epub 2025 Jun 20.
Cisplatin (CP) is a first-line platinum-based drug used for the treatment of head and neck cancer. However, tumor cells can diminish the therapeutic effects of CP through the detoxification system mediated by glutathione (GSH) and the nucleotide excision repair (NER) pathway. Herein, we present a light-activable and pH-responsive oxidative stress nanoamplifier (FPLC@IR OSNA), comprising an amphiphilic compound (FPLC) with Fmoc-lysine acting as a connector between a nitroimidazole derivative and a pH-responsive cinnamaldehyde (CA) derivative, loaded with photosensitizer IR780. The acidic microenvironment of the lysosome can trigger the release of CA to produce HO, which breaks down into oxygen, further improving the phototherapy efficacy mediated by IR780 irradiation. The consumption of oxygen during the phototherapy process induces hypoxia, prompting the reduction of nitroimidazole to aminoimidazole and leading to reduced GSH synthesis, enhancing tumor cell death induced by CP. Meanwhile, the accumulation of intracellular reactive oxygen species (ROS) during phototherapy attenuates the nuclear NER pathway, further augmenting the therapy effect of CP. This strategy, by combining FPLC@IR OSNA with laser and CP, significantly promotes the therapeutic effect in vitro and notably inhibits tumor growth in both Cal27 cell line-derived xenograft models and patient-derived xenograft models.
顺铂（CP）是一种用于治疗头颈癌的一线铂类药物。然而，肿瘤细胞可通过谷胱甘肽（GSH）介导的解毒系统和核苷酸切除修复（NER）途径降低CP的治疗效果。在此，我们展示了一种光激活且pH响应的氧化应激纳米放大器（FPLC@IR OSNA），它由一种两亲性化合物（FPLC）组成，其中Fmoc-赖氨酸作为硝基咪唑衍生物和pH响应性肉桂醛（CA）衍生物之间的连接体，并负载有光敏剂IR780。溶酶体的酸性微环境可触发CA的释放以产生羟基自由基（HO），其分解产生氧气，进一步提高由IR780照射介导的光疗效果。光疗过程中氧气的消耗诱导缺氧，促使硝基咪唑还原为氨基咪唑并导致GSH合成减少，增强CP诱导的肿瘤细胞死亡。同时，光疗过程中细胞内活性氧（ROS）的积累减弱了核NER途径，进一步增强了CP的治疗效果。这种将FPLC@IR OSNA与激光和CP相结合的策略，在体外显著促进了治疗效果，并且在Cal27细胞系来源的异种移植模型和患者来源的异种移植模型中均显著抑制了肿瘤生长。
