Selective in vivo metabolic cell-labeling-mediated cancer targeting.
Selective in vivo metabolic cell-labeling-mediated cancer targeting.
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选择性体内代谢细胞标记介导的癌症靶向
DOI：
10.1038/nchembio.2297
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发表时间：
2017-04
影响因子：
14.8
通讯作者：
Cheng J
中科院分区：
文献类型：
--
作者：
Wang H;Wang R;Cai K;He H;Liu Y;Yen J;Wang Z;Xu M;Sun Y;Zhou X;Yin Q;Tang L;Dobrucki IT;Dobrucki LW;Chaney EJ;Boppart SA;Fan TM;Lezmi S;Chen X;Yin L;Cheng J
通过表面受体区分癌细胞和正常细胞对于癌症诊断和靶向治疗至关重要。非天然糖的代谢糖工程为人工将化学受体引入细胞表面提供了一个强大的工具；然而，癌症选择性标记仍然是一个巨大的挑战。在此，我们报道了一种糖的设计，它可以在体外和体内选择性地标记癌细胞。具体地说，我们通过将四乙酰-N-叠氮乙酰甘露糖胺(Ac4ManAz)的异构乙酰基转化为可被癌症过度表达的酶选择性切割的笼形醚键，从而抑制了四乙酰-N-叠氮乙酰甘露糖胺(Ac4ManAz)的细胞标记活性，从而使叠氮基能够在癌细胞表面过度表达。组蛋白去乙酰化酶和组织蛋白L反应的乙酰化叠氮甘露胺是一种这样一种酶激活的Ac4ManAz类似物，它在体内开发了介导的癌症选择性标记，通过点击化学增加了二苯并环辛基-阿霉素结合物的肿瘤积累，并实现了对小鼠LS174T结肠癌、MDAMB-231三阴性乳腺癌和4T1转移性乳腺癌的靶向治疗。
Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. Herein we report the design of sugars that can selectively label cancer cells both in vitro and in vivo. Specifically, we inhibit the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) by converting its anomeric acetyl group to a caged ether bond that can be selectively cleaved by cancer-overexpressed enzymes and thus enables the overexpression of azido groups on the surface of cancer cells. Histone deacetylase and cathepsin L-responsive acetylated azidomannosamine, one such enzymatically activatable Ac4ManAz analog developed, mediated cancer-selective labeling in vivo, which enhanced tumor accumulation of a dibenzocyclooctyne–doxorubicin conjugate via click chemistry and enabled targeted therapy against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer and 4T1 metastatic breast cancer in mice.