A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging

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...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2018, Vol.9 (17), p.4185-4189
Main Authors: Stenton, Benjamin J, Oliveira, Bruno L, Matos, Maria J, Sinatra, Laura, Bernardes, Gonçalo J L
Format: Article
Language:English
Subjects:
Doxorubicin
Drug delivery systems
Palladium
Proteins
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Summary: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.
ISSN:2041-6520
2041-6539
DOI:10.1039/c8sc00256h