A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging.
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Type
Article
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Authors
Stenton, Benjamin J https://orcid.org/0000-0001-5852-2803
Oliveira, Bruno L https://orcid.org/0000-0002-7687-4746
Matos, Maria J https://orcid.org/0000-0002-3470-8299
Sinatra, Laura https://orcid.org/0000-0002-2467-3803
Bernardes, Gonçalo JL https://orcid.org/0000-0001-6594-8917
Abstract
We describe the development of a bifunctional linker that simultaneously allows site-specific protein modification and palladium-mediated bioorthogonal decaging. This was enabled by a thioether binding motif in the propargyl carbamate linker and a readily available palladium complex. We demonstrate the efficiency of this reaction by controlled drug release from a PEGylated doxorubicin prodrug in cancer cells. The linker can be easily installed into cysteine bearing proteins which we demonstrated for the construction of an anti-HER2 nanobody-drug conjugate. Targeted delivery of the nanobody drug conjugate showed effective cell killing in HER2+ cells upon palladium-mediated decaging.
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Keywords
0601 Biochemistry and Cell Biology, Biomedical, Cancer, Biotechnology, Cancer, 5.1 Pharmaceuticals
Journal Title
Chem Sci
Conference Name
Journal ISSN
2041-6520
2041-6539
2041-6539
Volume Title
9
Publisher
Royal Society of Chemistry (RSC)
Publisher DOI
Sponsorship
Engineering and Physical Sciences Research Council (EP/M003647/1)
The Royal Society (uf110046)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (702574)
European Research Council (676832)
European Commission (EC) (852985)
The Royal Society (uf110046)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (702574)
European Research Council (676832)
European Commission (EC) (852985)