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 (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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Breast Neoplasms / diagnosis
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Carbohydrates / analysis*
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Carbohydrates / chemical synthesis
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Carbohydrates / chemistry*
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Cell Line, Tumor
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Colonic Neoplasms / diagnosis
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / metabolism*
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Dose-Response Relationship, Drug
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Drug Design
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Drug Screening Assays, Antitumor
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Female
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Probes / analysis*
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Molecular Probes / chemical synthesis
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Molecular Probes / chemistry
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Molecular Probes / metabolism*
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Molecular Structure
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Molecular Targeted Therapy / methods*
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Neoplasms, Experimental / diagnosis
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism*
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Carbohydrates
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Molecular Probes
Associated data
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PubChem-Substance/322069299
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PubChem-Substance/322069310
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PubChem-Substance/322069312
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PubChem-Substance/322069313
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PubChem-Substance/322069314
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PubChem-Substance/322069315
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PubChem-Substance/322069316
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PubChem-Substance/322069317
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PubChem-Substance/322069318
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PubChem-Substance/322069300
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PubChem-Substance/322069301
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PubChem-Substance/322069302
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PubChem-Substance/322069303
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PubChem-Substance/322069304
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PubChem-Substance/322069305
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PubChem-Substance/322069306
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PubChem-Substance/322069307
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PubChem-Substance/322069308
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PubChem-Substance/322069309
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PubChem-Substance/322069311