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Selective in vivo metabolic cell-labeling-mediated cancer targeting
Hua Wang1, Ruibo Wang1, Kaimin Cai1
1Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
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.
Insights
Researchers developed novel sugars for precise cancer cell labeling, enhancing targeted therapy. This method uses cancer-specific enzymes to activate sugar modification, improving drug delivery and treatment efficacy in various cancer models.
Area of Science:
- Biochemistry
- Chemical Biology
- Molecular Oncology
Background:
- Distinguishing cancer cells from normal cells is crucial for effective cancer diagnosis and targeted therapies.
- Metabolic glycoengineering allows the introduction of chemical receptors on cell surfaces, but achieving cancer-selectivity remains challenging.
- Current methods lack the specificity needed for precise cancer cell targeting in vivo.
Purpose of the Study:
- To design and synthesize novel sugar analogs for selective cancer cell labeling.
- To develop a metabolic glycoengineering strategy that targets cancer cells based on their unique enzymatic environment.
- To demonstrate the in vitro and in vivo efficacy of cancer-selective labeling for enhanced targeted therapy.
Main Methods:
- Synthesized an enzymatically activatable analog of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) with a caged ether bond.
- Utilized cancer-overexpressed enzymes (histone deacetylase and cathepsin L) for selective cleavage of the cage.
- Applied click chemistry to link cell-surface azide groups to a doxorubicin conjugate for targeted drug delivery.
Main Results:
- The developed azidomannosamine analog selectively labeled cancer cells in vitro and in vivo.
- Enzymatic cleavage of the caged ether bond led to cancer-specific overexpression of azide groups on cell surfaces.
- Enhanced tumor accumulation of the doxorubicin conjugate was observed in LS174T colon, MDA-MB-231 triple-negative breast, and 4T1 metastatic breast cancer models.
- Successful targeted therapy was demonstrated in mouse models.
Conclusions:
- Developed a novel strategy for cancer-selective metabolic glycoengineering.
- Demonstrated the potential of enzymatically activatable sugars for precise cancer cell targeting.
- This approach significantly enhances the efficacy of targeted cancer therapy by improving drug delivery and accumulation.
