{"title":"Cascade-Activatable Nanoprodrug System Augments Sonochemotherapy of Bladder Cancer","authors":"Da-Yong Hou, Qing You, Peng Zhang, Xiang-Peng Li, Jiong-Cheng Wu, Yueze Wang, Hui-Hui You, Mei-Yu Lv, Gege Wu, Xiao Liu, Pengyu Guo, Dong-Bing Cheng, Xiaoyuan Chen, Wanhai Xu","doi":"10.1021/acsnano.4c12967","DOIUrl":null,"url":null,"abstract":"Sonochemotherapy (SCT) has emerged as a powerful modality for cancer treatment by triggering excessive production of reactive oxygen species (ROS) and controlled release of chemotherapeutic agents under ultrasound. However, achieving spatiotemporally controlled release of chemotherapeutic agents during ROS generation is still an enormous challenge. In this work, we developed a cascade-activated nanoprodrug (<b>CAN</b>) system that utilizes a reversible covalent Schiff base mixed with a hypoxia-activatable camptothecin (CPT) prodrug. Briefly, the designed fluorinated <b>CAN</b> system is self-assembled into nanoparticles under aqueous conditions, which could penetrate deep tumors to offer sufficient oxygen for ultrasound-triggered ROS production. Consequently, the nanoparticles substantially exacerbated the hypoxia of the tumor microenvironment (TME) by elevating oxygen consumption. The aggravated hypoxia in turn served as a positive amplifier to boost the tumor-specific CPT release of Azo-CPT prodrug, which made up for the insufficient treatment efficacy of sonodynamic therapy (SDT). On this basis, we observed a substantial reduction, approximately 3.5-fold, in the half-maximal inhibitory concentration (IC<sub>50</sub>) of the <b>CAN</b> system compared to that of free CPT in bladder cancer cell lines (T24). Furthermore, the <b>CAN</b> system demonstrated potent antitumor efficacy with reduced side effects, resulting in regression and eradication of T24 tumors in various mouse models. In summary, the <b>CAN</b> system can be easily extended by incorporating different chemotherapeutic agents, showing great potential to revolutionize the clinical management paradigm of bladder cancer.","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":"30 1","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Nano","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1021/acsnano.4c12967","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Sonochemotherapy (SCT) has emerged as a powerful modality for cancer treatment by triggering excessive production of reactive oxygen species (ROS) and controlled release of chemotherapeutic agents under ultrasound. However, achieving spatiotemporally controlled release of chemotherapeutic agents during ROS generation is still an enormous challenge. In this work, we developed a cascade-activated nanoprodrug (CAN) system that utilizes a reversible covalent Schiff base mixed with a hypoxia-activatable camptothecin (CPT) prodrug. Briefly, the designed fluorinated CAN system is self-assembled into nanoparticles under aqueous conditions, which could penetrate deep tumors to offer sufficient oxygen for ultrasound-triggered ROS production. Consequently, the nanoparticles substantially exacerbated the hypoxia of the tumor microenvironment (TME) by elevating oxygen consumption. The aggravated hypoxia in turn served as a positive amplifier to boost the tumor-specific CPT release of Azo-CPT prodrug, which made up for the insufficient treatment efficacy of sonodynamic therapy (SDT). On this basis, we observed a substantial reduction, approximately 3.5-fold, in the half-maximal inhibitory concentration (IC50) of the CAN system compared to that of free CPT in bladder cancer cell lines (T24). Furthermore, the CAN system demonstrated potent antitumor efficacy with reduced side effects, resulting in regression and eradication of T24 tumors in various mouse models. In summary, the CAN system can be easily extended by incorporating different chemotherapeutic agents, showing great potential to revolutionize the clinical management paradigm of bladder cancer.
期刊介绍:
ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.