Metal-coordinated oxidative stress amplifier to suppress tumor growth combined with M2 macrophage elimination

作     者：Chuyu Huang Zhishan Liu Linping Zhao Zuxiao Chen Rongrong Zheng Xiaona Rao Yuxuan Wei Xin Chen Shiying Li 

作者机构：The Fifth Affiliated HospitalGuangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacologythe NMPA and State Key Laboratory of Respiratory Diseasethe School of Pharmaceutical SciencesGuangzhou Medical University Department of Pulmonary and Critical Care MedicineZhujiang HospitalSouthern Medical University 

出 版 物：《Chinese Chemical Letters》 (中国化学快报(英文版))

年 卷 期：2024年第35卷第12期

页      面：220-225页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：financial support of National Key R&D Program of China (No. 2021YFD1800600) the National Natural Science Foundation of China (No. 32371394) the Guangdong Basic and Applied Basic Research Foundation (No. 2021B1515020043) the Special Projects in Key Areas of Colleges and Universities in Guangdong Province (No. 2022ZDZX2046) 

主　　题：Oxidative stress M2 macrophage Metal coordination Chemotherapy GSH degradation 

摘      要：The anti-oxidative characteristic and immunosuppressive microenvironment contribute to a high resistance of tumor to many treatments. In this work, a glutathione(GSH)-responsive metal-coordinated oxidative stress amplifier(designated as Cu PA) is fabricated to suppress tumor growth through elevating the cellular level of reactive oxygen species(ROS) and eliminating M2 macrophages. Among which,cooper ion(Cu2+) is capable of coordinating with thioredoxin(Trx) inhibitor of PX-12 and signal transducer and activator of transcription 6(STAT6) inhibitor of AS1517499 with the assistance of distearoyl phosphoethanolamine-PEG2000(DSPE-PEG2000), which can extensively increase the stability to enhance drug delivery in vitro and in vivo. Furthermore, CuPA can upregulate intracellular ROS to cause tumor cell death through restraining Trx and degrading GSH. Also, Cu PA-mediated STAT6 inhibition results in the elimination of M2 macrophage to reverse the immunosuppressive tumor microenvironment. Finally,the elevated oxidative stress and increased immune activation amplify the synergistic antitumor effect without causing obvious side effect. This work provides a new sight for synergistic tumor suppression through chemo-immunotherapy in consideration of the complex resistant tumor microenvironment.