A Synthetic Hybrid Molecule for the Selective Removal of Human Pluripotent Stem Cells from Cell Mixtures

被引：14

作者：

Mao, Di ^{[1
,2
]}

Ando, Shin ^{[1
,2
]}

Sato, Shin-ichi ^{[1
,2
]}

Qin, Ying ^{[1
,2
]}

Hirata, Nao ^{[1
,2
]}

Katsuda, Yousuke ^{[1
,2
]}

Kawase, Eihachiro ^{[3
]}

Kuo, Ting-Fang ^{[1
,2
]}

Minami, Itsunari ^{[4
]}

Shiba, Yuji ^{[5
,6
]}

Ueda, Kazumitsu

Nakatsuji, Norio ^{[7
,8
]}

Uesugi, Motonari ^{[1
,2
,9
,10
]}

机构：

[1] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Uji, Kyoto 6110011, Japan

[2] Kyoto Univ, Inst Chem Res, Uji, Kyoto 6110011, Japan

[3] Kyoto Univ, Inst Frontier Med Sci, Kyoto 6068507, Japan

[4] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Kyoto 6068501, Japan

[5] Shinshu Univ, Inst Biomed Sci, Matsumoto, Nagano 3908621, Japan

[6] Shinshu Univ, Sch Med, Dept Cardiovasc Med, Matsumoto, Nagano 3908621, Japan

[7] Kyoto Univ, Inst Frontier Med Sci, Kyoto 6068507, Japan

[8] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Kyoto 6068507, Japan

[9] Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Kyoto 6068502, Japan

[10] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Kyoto 6068502, Japan

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2017年 / 56卷 / 07期

关键词：

ABC transporters; cytotoxicity; drug conjugates; fluorescent probes; stem cell therapy; MULTIDRUG-RESISTANCE; CYTOTOXIC ANTIBODY; INHIBITOR; CAMPTOTHECIN; ELIMINATION; PROTEIN; CARDIOMYOCYTES; TRANSPORTERS; CANCER; ANALOG;

D O I：

10.1002/anie.201610284

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

A major hurdle in stem cell therapy is the tumorigenic risk of residual undifferentiated stem cells. This report describes the design and evaluation of synthetic hybrid molecules that efficiently reduce the number of human induced pluripotent stem cells (hiPSCs) in cell mixtures. The design takes advantage of Kyoto probe1 (KP-1), a fluorescent chemical probe for hiPSCs, and clinically used anticancer drugs. Among the KP-1-drug conjugates we synthesized, we found an exceptionally selective, chemically tractable molecule that induced the death of hiPSCs. Mechanistic analysis suggested that the high selectivity originates from the synergistic combination of transporter-mediated efflux and the cytotoxicity mode of action. The present study offers a chemical and mechanistic rationale for designing selective, safe, and simple reagents for the preparation of non-tumorigenic clinical samples.

引用

页码：1765 / 1770

页数：6

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