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PUBLISHED ONLINE: 13 FEBRUARY 2017 | http://dx.doi.org/10.1038/nchembio.2297
Web End =DOI: 10.1038/NCHEMBIO.2297
Selective in vivo metabolic cell-labeling-mediated cancer targeting
Hua Wang1,14, Ruibo Wang1,14, Kaimin Cai1,14, Hua He2, Yang Liu1, Jonathan Yen3, Zhiyu Wang1, Ming Xu1, Yiwen Sun1, Xin Zhou4, Qian Yin1, Li Tang1, Iwona T Dobrucki5, Lawrence W Dobrucki3, Eric J Chaney5, Stephen A Boppart3,57, Timothy M Fan8, Stphane Lezmi9, Xuesi Chen10*,
Lichen Yin2* & Jianjun Cheng13,5,1113*
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 dibenzocyclooctynedoxorubicin 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.
2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Cell-surface receptors play a vital role in regulating the interactions between cells and the extracellular microenvironment13. There has been consensus that the recognition of
disease-specific, cell-surface receptors enables the targeted delivery of therapeutic agents to diseased tissues and minimizes undesired side effects. Based on lineage-specific genome sequences, different cell types possess varying populations of cell-surface receptors46.
Additionally, diseased cells harboring genetic mutations have the capacity to express altered receptor populations79. For instance, as a consequence of gene amplification, some breast cancer cells over-express human epidermal growth factor receptor 2 (HER2/neu), which fosters the development of various cancer-targeting drugs1012.
However, the differences in endogenous receptor populations between diseased and normal cells cannot always be exploited as therapeutic targets, as they might be too small to impart high selectivity, or specific receptors may simply not be expressed by the target cells of interest1315. For...