title: Imaging the intracellular distribution of tyrosine kinase inhibitors in living cells with quantitative hyperspectral stimulated Raman scattering.
abstract: ABL1 tyrosine-kinase inhibitors (TKI) are front-line therapy for chronic myelogenous leukaemia and are among the best-known examples of targeted cancer therapeutics. However, the dynamic uptake into cells of TKIs of low molecular weight and their intracellular behaviour is unknown because of 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. Concentrations of both drugs were enriched over 1,000-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 more than tenfold when chloroquine is used simultaneously, which suggests that chloroquine may increase the efficacy of TKIs through lysosome-mediated drug-drug interaction in addition to the commonly proposed autophagy-inhibition mechanism.
authors.affiliation: 1] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA [2].
authors.forename: Dan
authors.initials: D
authors.lastname: Fu
authors.affiliation: 1] Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA [2].
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Wenjing Suzanne
authors.initials: WS
authors.lastname: Zhu
authors.affiliation: Novartis Institute for Biomedical Research, Basel CH-4002, Switzerland.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.affiliation: Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Y Karen
authors.initials: YK
authors.lastname: Wang
authors.affiliation: Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Tami
authors.initials: T
authors.lastname: Hood
authors.affiliation: Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wylie
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: X Sunney
authors.initials: XS
authors.lastname: Xie
mesh_terms: D058948:Cell Tracking / Q000379:methods*; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013059:Spectrum Analysis, Raman / Q000379:methods*
chemical_list: D047428:Protein Kinase Inhibitors