Imaging the Intracellular Distribution of Tyrosine Kinase Inhibitors in Living Cells with Quantitative Hyperspectral Stimulated Raman Scattering
Zhu, Wenjing Suzanne
Manley, Paul W.
Wang, Y. Karen
Xie, X. Sunney
MetadataShow full item record
CitationFu, Dan, Jing Zhou, Wenjing Suzanne Zhu, Paul W. Manley, Y. Karen Wang, Tami Hood, Andrew Wylie, and X. Sunney Xie. 2014. “Imaging the Intracellular Distribution of Tyrosine Kinase Inhibitors in Living Cells with Quantitative Hyperspectral Stimulated Raman Scattering.” Nature chemistry 6 (7): 614-622. doi:10.1038/nchem.1961. http://dx.doi.org/10.1038/nchem.1961.
AbstractABL1 tyrosine-kinase inhibitors (TKI) are a front-line therapy for chronic myelogenous leukemia and represent the best known examples of targeted cancer therapeutics. However, the dynamic uptake of low molecular weight TKIs into cells and their intracellular behavior is largely unknown due to the difficulty of observing non-fluorescent small molecules at subcellular resolution. Here we report the direct label-free visualization and quantification of two TKI drugs – imatinib and nilotinib inside living cells using hyperspectral stimulated Raman scattering imaging. Both drugs were enriched over 1000-fold in lysosomes as a result of their lysosomotropic properties. In addition, low solubility appeared to contribute significantly to the surprisingly large accumulation of nilotinib. We further show that the lysosomal trapping of imatinib was reduced by more than 10-fold when using chloroquine simultaneously, suggesting that chloroquine may increase the efficacy of TKIs through lysosome mediated drug-drug interaction besides the commonly proposed autophagy inhibition mechanism.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13890656
- FAS Scholarly Articles