A novel prodrug and its nanoformulation suppress cancer stem cells by inducing immunogenic cell death and inhibiting indoleamine 2, 3-dioxygenase

Jiankun Guan; Yuxin Wu; Xin Liu; Huimin Wang; Ningbing Ye; Zheng Li; Chen Xiao; Zhijie Zhang; Zifu Li; Xiangliang Yang

doi:10.1016/j.biomaterials.2021.121180

A novel prodrug and its nanoformulation suppress cancer stem cells by inducing immunogenic cell death and inhibiting indoleamine 2, 3-dioxygenase

Biomaterials. 2021 Dec:279:121180. doi: 10.1016/j.biomaterials.2021.121180. Epub 2021 Oct 9.

Authors

Jiankun Guan¹, Yuxin Wu¹, Xin Liu¹, Huimin Wang¹, Ningbing Ye¹, Zheng Li¹, Chen Xiao¹, Zhijie Zhang¹, Zifu Li², Xiangliang Yang³

Affiliations

¹ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
² National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Wuhan Institute of Biotechnology, High Tech Road 666, East Lake High Tech Zone, Wuhan, 430040, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China. Electronic address: zifuli@hust.edu.cn.
³ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, PR China; GBA Research Innovation Institute for Nanotechnology, Guangdong, 510530, PR China.

PMID: 34768152
DOI: 10.1016/j.biomaterials.2021.121180

Abstract

Cancer stem cells (CSCs) present grand challenges for triple-negative breast cancer (TNBC). Conventional chemotherapy drugs, including Camptothecin (CPT), not only cannot eradicate CSCs but also foster a suppressive immune microenvironment for the initiation and proliferation of CSCs. Herein, we report a novel prodrug CPT-SS-NLG919 (CN) and its nanoformulation CN@PLA-HES-FA (CN@PHF), which potently suppress CSCs by regulating CSCs niche in murine TNBC 4T1 tumors. Via inducing immunogenic cell death (ICD) and simultaneous inhibiting indoleamine 2, 3-dioxygenase (IDO), CN and CN@PHF promote DC maturation, decrease Treg cells, mitigate tryptophan consumption, and reduce the amount of IL-6, IL-13, and TGF-β, converting CSCs niche to a hostile condition for CSCs to live in and eliminating CSCs efficiently, thereby inducing efficient tumor inhibition in 4T1 tumor models. Our work represents a new paradigm of eliminating CSCs by regulating tumor immune microenvironment and suggests that CN and its nanoformulation CN@PHF are promising candidates for the treatment of intractable TNBC.

Keywords: 3-Dioxygenase; Camptothecin; Cancer stem cells; Immunogenic cell death; Indoleamine 2; NLG919.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Dioxygenases*
Immunogenic Cell Death
Immunotherapy
Indoleamine-Pyrrole 2,3,-Dioxygenase
Mice
Neoplasms*
Neoplastic Stem Cells
Prodrugs* / pharmacology

Substances

Indoleamine-Pyrrole 2,3,-Dioxygenase
Prodrugs
Dioxygenases