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A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging
Benjamin J Stenton1, Bruno L Oliveira1, Maria J Matos1
1Department of Chemistry , University of Cambridge , Lensfield Road , CB2 1EW Cambridge , UK .
Chemical Science
|May 22, 2018
Summary
Researchers developed a novel bifunctional linker for site-specific protein modification and palladium-triggered drug release. This linker enables targeted cancer cell killing via antibody-drug conjugates, showcasing its potential in precision medicine.
Area of Science:
- Chemical Biology
- Bioconjugation Chemistry
- Drug Delivery Systems
Background:
- Site-specific protein modification is crucial for developing targeted therapeutics.
- Bioorthogonal chemistry enables precise molecular manipulations within biological systems.
- Palladium-mediated reactions offer unique opportunities for controlled molecular activation.
Purpose of the Study:
- To develop a bifunctional linker enabling simultaneous site-specific protein modification and palladium-mediated bioorthogonal decaging.
- To demonstrate controlled drug release from a prodrug in cancer cells.
- To construct and evaluate an anti-HER2 nanobody-drug conjugate for targeted cancer therapy.
Main Methods:
- Design and synthesis of a propargyl carbamate linker with a thioether binding motif.
- Installation of the linker into cysteine-bearing proteins.
- Development of a palladium-mediated bioorthogonal decaging strategy.
- Preparation and in vitro testing of a PEGylated doxorubicin prodrug and an anti-HER2 nanobody-drug conjugate.
Main Results:
- The bifunctional linker successfully enabled site-specific protein modification and palladium-mediated bioorthogonal decaging.
- Controlled doxorubicin release was achieved from a PEGylated prodrug in cancer cells.
- An anti-HER2 nanobody-drug conjugate was constructed, demonstrating effective cell killing in HER2+ cells upon palladium-mediated decaging.
Conclusions:
- The developed bifunctional linker is efficient for site-specific protein modification and bioorthogonal drug release.
- This technology facilitates the creation of targeted antibody-drug conjugates for cancer therapy.
- Palladium-mediated decaging offers a promising strategy for controlled drug delivery and activation in cancer cells.
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