Building bioorthogonal click-release capable artificial receptors on cancer cell surface for imaging, drug targeting
Jing Chen1, Peng Ji1, Giri Gnawali1
1Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
Abstract:
The current targeting drug delivery mainly relies on cancer cell surface receptors. However, in many cases, binding affinities between protein receptors and homing ligands is relatively low and the expression level between cancer and normal cells is not significant. Distinct from conventional targeting strategies, we have developed a general cancer targeting platform by building artificial receptor on cancer cell surface via a chemical remodeling of cell surface glycans. A new tetrazine (Tz) functionalized chemical receptor has been designed and efficiently installed on cancer cell surface as "overexpressed" biomarker through a metabolic glycan engineering. Different from the reported bioconjugation for drug targeting, the tetrazine labeled cancer cells not only locally activate TCO-caged prodrugs but also release active drugs via the unique bioorthogonal Tz-TCO click-release reaction. The studies have demonstrated that the new drug targeting strategy enables local activation of prodrug, which ultimately leads to effective and safe cancer therapy.
Insights
This study introduces a novel cancer targeting platform using artificial receptors on cell surfaces. This method enhances drug delivery by locally activating prodrugs, leading to safer and more effective cancer therapies.
Area of Science:
- Biochemistry
- Chemical Biology
- Oncology
Background:
- Conventional cancer drug delivery often targets cell surface receptors with limited binding affinity and specificity.
- Differences in receptor expression between cancer and normal cells are frequently insufficient for precise targeting.
Purpose of the Study:
- To develop a general cancer targeting platform by creating artificial receptors on cancer cell surfaces.
- To engineer a novel method for localized prodrug activation and drug release.
Main Methods:
- Utilized metabolic glycan engineering to install tetrazine (Tz) functionalized chemical receptors on cancer cell surfaces.
- Employed a bioorthogonal tetrazine-TCO click-release reaction for prodrug activation and drug release.
Main Results:
- Successfully engineered cancer cells with artificial "overexpressed" biomarkers via chemical remodeling of cell surface glycans.
- Demonstrated localized activation of TCO-caged prodrugs by tetrazine-labeled cancer cells.
- Showcased the efficacy of the unique bioorthogonal click-release reaction for drug delivery.
Conclusions:
- The developed platform offers a new strategy for cancer targeting drug delivery.
- This approach enables precise, localized prodrug activation, enhancing therapeutic effectiveness.
- The method promises safer and more effective cancer treatment by minimizing off-target effects.
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