Selective in vivo metabolic cell-labeling-mediated cancer targeting

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.

Polyvalent Display of Biomolecules on Live Cells

“…[6] As the cell surface displays the azide groups, a molecule bearing dibenzocyclooctyne (DBCO) would react with the membrane glycoproteins via copper-free click chemistry. [11,12] The results (Figure S1) showed that the surface of the Ac 4 ManNAz-fed cells could display DI after treated with DI-DBCO. While we applied Ac 4 ManNAz for DI display, it is possible to use other methods to realize the same purpose.…”

Engineering Cell Membrane‐Based Nanotherapeutics to Target Inflammation

“…[40] Then, MDT-activated TGF-β1 was immobilized onto the azidefunctionalized antigen-presenting cell (APC) surface through a mild biorthogonal reaction, providing ease in translating this strategy to innumerable biomaterial platforms to modulate the transplant environment. [42] This so-called Adv. [41] Nanoparticles with a hydrazine moiety could be conjugated to the aldehyde groups to form stable secondary amine linkages through the Mannich reaction ( Figure 2F).…”

“…[44] Then, the magnetic nanoclusters (MNCs) were cloaked with engineered membranederived vesicles to form artificial APCs, leading to more efficient T-cell expansion and increased cytotoxicity. [42] Copyright 2017, Nature Publishing Group. Reproduced with permission.…”

Chemical and Enzymatic Strategies for Bacterial and Mammalian Cell Surface Engineering

“…Subsequent click chemistry allows the delivery of alkyne labeled dibenzocyclooctyne‐doxorubicin to the cancer cells. Such a strategy enabled targeted therapy and substantially reduced toxicity on noncancerous cells . Therefore, metabolic engineering approach offers unprecedented opportunities to study the biological functions of cell surface glycans or develop novel therapeutics for disease treatment.…”