Restoration of the Immunogenicity of Tumor Cells for Enhanced Cancer Therapy via Nanoparticle-Mediated Copper Chaperone Inhibition
Feixiang Ding
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorFei Li
Department of Chemical Biology, State Key Laboratory of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 P. R. China
Search for more papers by this authorDongsheng Tang
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 P. R. China
Search for more papers by this authorBin Wang
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 P. R. China
Search for more papers by this authorJunyan Liu
Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Search for more papers by this authorProf. Xiaoyuan Mao
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorProf. Jiye Yin
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Haihua Xiao
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Jing Wang
Department of Chemical Biology, State Key Laboratory of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Zhaoqian Liu
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorFeixiang Ding
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorFei Li
Department of Chemical Biology, State Key Laboratory of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 P. R. China
Search for more papers by this authorDongsheng Tang
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 P. R. China
Search for more papers by this authorBin Wang
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 P. R. China
Search for more papers by this authorJunyan Liu
Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Search for more papers by this authorProf. Xiaoyuan Mao
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorProf. Jiye Yin
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Haihua Xiao
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Jing Wang
Department of Chemical Biology, State Key Laboratory of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Zhaoqian Liu
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 P. R. China
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078 P. R. China
Search for more papers by this authorGraphical Abstract
A combination strategy for synergistic chemo-sensitization and conversion of tumor cells into vaccines triggers an intense immune response through copper chaperone inhibition with multifunctional nanoparticles loaded with cisplatin prodrugs and DC_AC50 conjugated to reactive oxygen species (ROS)-responsive polymers.
Abstract
Recent progress in studying copper-dependent targets and pathways in the context of tumor treatment has provided new insights into therapeutic strategies of leveraging copper-dependent disease vulnerabilities and pharmacological manipulation of intratumor copper transportation to improve chemotherapy. Here, we developed reactive oxygen species (ROS)-sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(IV) prodrug. The released DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1-ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin and inducing significant ROS generation. Excessive ROS then elicits intense endoplasmic reticulin (ER) stress which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Our study suggests that nanoparticle-mediated copper chaperone inhibition via DC_AC50 can restore the immunogenicity of tumor cells for enhanced chemotherapy and cancer immunotherapy.
Conflict of interest
The authors declare no conflicts of interest.
Supporting Information
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