Selective in vivo metabolic cell-labeling-mediated cancer targeting

Hua Wang, Ruibo Wang, Kaimin Cai, Hua He, Yang Liu, Jonathan Yen, Zhiyu Wang, Ming Xu, Yiwen Sun, Xin Zhou, Qian Yin, Li Tang, Iwona T. Dobrucki, Lawrence W. Dobrucki, Eric J. Chaney, Stephen A. Boppart, Timothy M. Fan, Stéphane Lezmi, Xuesi Chen, Lichen YinJianjun Cheng

Research output: Contribution to journalArticle

Abstract

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 (Ac4 ManAz) 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 Ac4 ManAz 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.

Original languageEnglish (US)
Pages (from-to)415-424
Number of pages10
JournalNature chemical biology
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2017

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Neoplasms
Cell Surface Receptors
Click Chemistry
Triple Negative Breast Neoplasms
Cathepsin L
Histone Deacetylases
Ether
Doxorubicin
Colonic Neoplasms
Breast Neoplasms
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Selective in vivo metabolic cell-labeling-mediated cancer targeting. / Wang, Hua; Wang, Ruibo; Cai, Kaimin; He, Hua; Liu, Yang; Yen, Jonathan; Wang, Zhiyu; Xu, Ming; Sun, Yiwen; Zhou, Xin; Yin, Qian; Tang, Li; Dobrucki, Iwona T.; Dobrucki, Lawrence W.; Chaney, Eric J.; Boppart, Stephen A.; Fan, Timothy M.; Lezmi, Stéphane; Chen, Xuesi; Yin, Lichen; Cheng, Jianjun.

In: Nature chemical biology, Vol. 13, No. 4, 01.04.2017, p. 415-424.

Research output: Contribution to journalArticle

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 2017, 'Selective in vivo metabolic cell-labeling-mediated cancer targeting', Nature chemical biology, vol. 13, no. 4, pp. 415-424. https://doi.org/10.1038/nchembio.2297
Wang, Hua ; Wang, Ruibo ; Cai, Kaimin ; He, Hua ; Liu, Yang ; Yen, Jonathan ; Wang, Zhiyu ; Xu, Ming ; Sun, Yiwen ; Zhou, Xin ; Yin, Qian ; Tang, Li ; Dobrucki, Iwona T. ; Dobrucki, Lawrence W. ; Chaney, Eric J. ; Boppart, Stephen A. ; Fan, Timothy M. ; Lezmi, Stéphane ; Chen, Xuesi ; Yin, Lichen ; Cheng, Jianjun. / Selective in vivo metabolic cell-labeling-mediated cancer targeting. In: Nature chemical biology. 2017 ; Vol. 13, No. 4. pp. 415-424.
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