Imaging the Intracellular Distribution of Tyrosine Kinase Inhibitors in Living Cells with Quantitative Hyperspectral Stimulated Raman Scattering

Overview

Journal Nat Chem

Specialty Chemistry

Date 2014 Jun 21

PMID 24950332

Citations 116

Authors

Dan Fu

Jing Zhou

Wenjing Suzanne Zhu

Paul W Manley

Y Karen Wang

Tami Hood

Andrew Wylie

X Sunney Xie

Affiliations

Soon will be listed here.

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.

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