A novel prodrug and its nanoformulation suppress cancer stem cells by inducing immunogenic cell death and inhibiting indoleamine 2, 3-dioxygenase. (December 2021)

• Record Type: Journal Article
• Authors: Guan, Jiankun; Wu, Yuxin; Liu, Xin; Wang, Huimin; Ye, Ningbing; Li, Zheng; Xiao, Chen; Zhang, Zhijie; Li, Zifu; Yang, Xiangliang
• Is Part Of: Biomaterials. Volume 279(2021)
• Publication Date: 2021-12
• Subjects: Cancer stem cells -- Immunogenic cell death -- Indoleamine 2 -- 3-Dioxygenase -- Camptothecin -- NLG919; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2021.121180
• Languages: English
• ISSNs: 0142-9612

Abstract

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. Highlights: Combining ICD induction and IDO inhibition can modulate CSCs niche, relieve CSCs dormancy and eliminate CSCs. A novel prodrug CN has good activity in inducing ICD and inhibiting IDO, thereby efficient inhibiting TNBC tumors. CN@PHF remodel CSCs niche by promoting DC maturation, reducing Treg cells, tryptophan consumption, IL-6, IL-13, and TGF-β.