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Live Cell Labeling with Terpyridine Derivative Proligands to Measure Cytotoxicity Mediated by Immune Cells
ChemMedChem ( IF 3.6 ) Pub Date : 2017-12-04 , DOI: 10.1002/cmdc.201700626
Yuki Sakai 1 , Satoshi Mizuta 1 , Asuka Kumagai 1 , Mohammed S. O. Tagod 1 , Hiroaki Senju 2 , Tatsufumi Nakamura 3 , Craig T. Morita 4 , Yoshimasa Tanaka 1
Affiliation  

Immunotherapy using immune checkpoint inhibitors and CAR‐T cells has revolutionized treatment for patients with malignant tumors. However, measuring tumor cell cytotoxicity mediated by immune effector cells in clinical laboratories has been difficult due to the requirement for radioactive substances. In this study, a series of novel terpyridine derivative proligands were synthesized, and a non‐radioactive cellular cytotoxicity assay using the newly synthesized compounds was developed for use in preclinical and clinical studies for cancer immunotherapy. Once internalized into target cells, the compounds are hydrolyzed by esterases, resulting in the intracellular accumulation of the negatively charged terpyridine derivatives. When the labeled target cells are recognized and killed by immune effector cells, the integrity of the cell membrane is disrupted, and the terpyridine derivatives are released. Upon combining the culture supernatant with europium (Eu3+), the cytotoxicity of immune effector cells for the target cells can be quantitatively determined by measuring the intensity of the Eu3+/ligand‐derived time‐resolved fluorescence. Thus, the assay developed in this study would facilitate the development of novel cancer immunotherapies.

中文翻译:

用三联吡啶衍生物配体进行活细胞标记以测量免疫细胞介导的细胞毒性

使用免疫检查点抑制剂和CAR‐T细胞的免疫疗法彻底改变了恶性肿瘤患者的治疗方法。然而,由于对放射性物质的需求,在临床实验室中测量由免疫效应细胞介导的肿瘤细胞的细胞毒性已经很困难。在这项研究中,合成了一系列新型的吡啶吡啶衍生物配体,并开发了使用新合成的化合物的非放射性细胞毒性试验,用于癌症免疫疗法的临床前和临床研究。一旦内化到靶细胞中,这些化合物就被酯酶水解,导致带负电荷的三联吡啶衍生物在细胞内积累。当标记的靶细胞被免疫效应细胞识别并杀死后,细胞膜的完整性被破坏,并且三联吡啶衍生物被释放。将培养上清液与euro(Eu3+),可以通过测量Eu 3+ /配体衍生的时间分辨荧光的强度来定量确定免疫效应细胞对靶细胞的细胞毒性。因此,在这项研究中开发的测定将促进新型癌症免疫疗法的发展。
更新日期:2017-12-04
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