{"title":"氧化应激放大和抗氧化防御破坏的工程纳米药物增强癌症治疗。","authors":"Xiaoya Wu, Jianxin Rong, Yingjian Cui, Jiahui Cong, Xiongwei Qu and Xiuli Hu*, ","doi":"10.1021/acs.jmedchem.5c01817","DOIUrl":null,"url":null,"abstract":"<p >Photodynamic therapy (PDT) faces limitations due to tumor hypoxia and antioxidant defenses. Herein, a modular drug delivery system (P@Ce6/PTX) that integrates photosensitizer (Ce6), metal ion (Cu<sup>2+</sup>), and hypoxia-activated paclitaxel prodrugs (PTX-MTZ) was developed by a one-step coassembly strategy to amplify oxidative stress-induced ferroptosis while enabling hypoxia-triggered chemotherapy. The Cu<sup>2+</sup>-imidazole coordination not only stabilizes the nanostructure but also facilitates controllable size modulation by varying the polymer-to-metal ratio. Upon laser irradiation, Ce6 generates cytotoxic ROS to induce DNA damage while exacerbating hypoxia, which triggers PTX-MTZ reduction and PTX/MTZ release. MTZ consumes NADPH or GSH to sensitize PDT via inhibiting DNA repair and aggravates the antioxidant system. The reported multimodulating nanomedicine exhibits spatiotemporal controllable PDT, Cu<sup>2+</sup>-amplified ferroptosis through lipid peroxidation, and hypoxia-activated chemotherapy, achieving 92.3% tumor regression rate with minimal off-target toxicity.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 15","pages":"16819–16832"},"PeriodicalIF":6.8000,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Engineering Nanomedicine with Oxidative Stress Amplification and Antioxidant Defense Disruption for Enhanced Cancer Treatment\",\"authors\":\"Xiaoya Wu, Jianxin Rong, Yingjian Cui, Jiahui Cong, Xiongwei Qu and Xiuli Hu*, \",\"doi\":\"10.1021/acs.jmedchem.5c01817\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Photodynamic therapy (PDT) faces limitations due to tumor hypoxia and antioxidant defenses. Herein, a modular drug delivery system (P@Ce6/PTX) that integrates photosensitizer (Ce6), metal ion (Cu<sup>2+</sup>), and hypoxia-activated paclitaxel prodrugs (PTX-MTZ) was developed by a one-step coassembly strategy to amplify oxidative stress-induced ferroptosis while enabling hypoxia-triggered chemotherapy. The Cu<sup>2+</sup>-imidazole coordination not only stabilizes the nanostructure but also facilitates controllable size modulation by varying the polymer-to-metal ratio. Upon laser irradiation, Ce6 generates cytotoxic ROS to induce DNA damage while exacerbating hypoxia, which triggers PTX-MTZ reduction and PTX/MTZ release. MTZ consumes NADPH or GSH to sensitize PDT via inhibiting DNA repair and aggravates the antioxidant system. The reported multimodulating nanomedicine exhibits spatiotemporal controllable PDT, Cu<sup>2+</sup>-amplified ferroptosis through lipid peroxidation, and hypoxia-activated chemotherapy, achieving 92.3% tumor regression rate with minimal off-target toxicity.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"68 15\",\"pages\":\"16819–16832\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-07-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01817\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01817","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Engineering Nanomedicine with Oxidative Stress Amplification and Antioxidant Defense Disruption for Enhanced Cancer Treatment
Photodynamic therapy (PDT) faces limitations due to tumor hypoxia and antioxidant defenses. Herein, a modular drug delivery system (P@Ce6/PTX) that integrates photosensitizer (Ce6), metal ion (Cu2+), and hypoxia-activated paclitaxel prodrugs (PTX-MTZ) was developed by a one-step coassembly strategy to amplify oxidative stress-induced ferroptosis while enabling hypoxia-triggered chemotherapy. The Cu2+-imidazole coordination not only stabilizes the nanostructure but also facilitates controllable size modulation by varying the polymer-to-metal ratio. Upon laser irradiation, Ce6 generates cytotoxic ROS to induce DNA damage while exacerbating hypoxia, which triggers PTX-MTZ reduction and PTX/MTZ release. MTZ consumes NADPH or GSH to sensitize PDT via inhibiting DNA repair and aggravates the antioxidant system. The reported multimodulating nanomedicine exhibits spatiotemporal controllable PDT, Cu2+-amplified ferroptosis through lipid peroxidation, and hypoxia-activated chemotherapy, achieving 92.3% tumor regression rate with minimal off-target toxicity.
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.