一种新型前药及其纳米制剂通过诱导免疫原性细胞死亡和抑制吲哚胺 2,3-双加氧酶来抑制肿瘤干细胞。
A novel prodrug and its nanoformulation suppress cancer stem cells by inducing immunogenic cell death and inhibiting indoleamine 2, 3-dioxygenase.
机构信息
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
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.
出版信息
Biomaterials. 2021 Dec;279:121180. doi: 10.1016/j.biomaterials.2021.121180. Epub 2021 Oct 9.
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.
癌症干细胞 (CSCs) 对三阴性乳腺癌 (TNBC) 提出了巨大挑战。传统的化疗药物，包括喜树碱 (CPT)，不仅不能根除 CSCs，还会促进 CSCs 的起始和增殖的抑制性免疫微环境。在此，我们报告了一种新型前药 CPT-SS-NLG919 (CN) 和其纳米制剂 CN@PLA-HES-FA (CN@PHF)，它们通过调节小鼠 TNBC 4T1 肿瘤中的 CSCs 生态位，有效地抑制 CSCs。通过诱导免疫原性细胞死亡 (ICD) 和同时抑制吲哚胺 2,3-双加氧酶 (IDO)，CN 和 CN@PHF 促进 DC 成熟，减少 Treg 细胞，减轻色氨酸消耗，并减少 IL-6、IL-13 和 TGF-β 的量，将 CSCs 生态位转化为不利于 CSCs 生存的条件，并有效地消除 CSCs，从而在 4T1 肿瘤模型中诱导有效的肿瘤抑制。我们的工作代表了通过调节肿瘤免疫微环境来消除 CSCs 的新范例，并表明 CN 和其纳米制剂 CN@PHF 是治疗难治性 TNBC 的有前途的候选药物。
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