Claudio Vinegoni, Ph.D. | Quantitating drug-target engagement in single cells in vitro and in vivo

Nat. Chem. Biol.
Quantitating drug-target engagement in single cells in vitro and in vivo

Dubach, J. M., Kim, E., Yang, K., Cuccarese, M., Giedt, R. J., Meirnetis, L. G., Vinegoni^#, C., and Weissleder^#, R.

Nature Chemical Biology 2017

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Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target. We then determined average in vivo tumor concentrations and found marked population heterogeneity following systemic delivery, revealing single cells with low target occupancy at high average target engagement in vivo.
@article{2017-NCBIOL, author= {Dubach, J. M. and Kim, E. and Yang, K. and Cuccarese, M. and Giedt, R. J. and Meirnetis, L. G. and Vinegoni<sup>#</sup>, C. and Weissleder<sup>#</sup>, R.}, title= {Quantitating drug-target engagement in single cells in vitro and in vivo}, journal= {Nature Chemical Biology}, alternatejournal = {Nat. Chem. Biol.}, year = {2017}, volume = {13}, number = {2}, pages = {168-173}, issn = {1552-4450}, doi = {10.1038/nchembio.2248}, pmcid = {PMC5630128}, pmid= {27918558} }
27918558

PMC5630128

10.1038/nchembio.2248

Abstract

"Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target. We then determined average in vivo tumor concentrations and found marked population heterogeneity following systemic delivery, revealing single cells with low target occupancy at high average target engagement in vivo."

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For attribution in academic contexts, please cite this work as:

Dubach, J. M., Kim, E., Yang, K., Cuccarese, M., Giedt, R. J., Meirnetis, L. G., Vinegoni^#, C., & Weissleder^#, R. (2017). Quantitating drug-target engagement in single cells in vitro and in vivo. Nature Chemical Biology, 13(2), 168–173. https://doi.org/10.1038/nchembio.2248