Live Cell Labeling with Terpyridine Derivative Proligands to Measure Cytotoxicity Mediated by Immune Cells

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2017 Nov 8

PMID 29110403

Citations 8

Authors

Yuki Sakai

Satoshi Mizuta

Asuka Kumagai

Mohammed S O Tagod

Hiroaki Senju

Tatsufumi Nakamura

Craig T Morita

Yoshimasa Tanaka

Affiliations

Soon will be listed here.

Abstract

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 (Eu ), the cytotoxicity of immune effector cells for the target cells can be quantitatively determined by measuring the intensity of the Eu /ligand-derived time-resolved fluorescence. Thus, the assay developed in this study would facilitate the development of novel cancer immunotherapies.

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