Polymyxin is the last-line therapy
against Gram-negative ‘superbugs’;
however, dose-limiting nephrotoxicity can occur in up to 60% of patients
after intravenous administration. Understanding the accumulation and
concentration of polymyxin within renal tubular cells is essential
for the development of novel strategies to ameliorate its nephrotoxicity
and to develop safer, new polymyxins. We designed and synthesized
a novel dual-modality iodine-labeled fluorescent probe for quantitative
mapping of polymyxin in kidney proximal tubular cells. Measured by
synchrotron X-ray fluorescence microscopy, polymyxin concentrations
in single rat (NRK-52E) and human (HK-2) kidney tubular cells were
approximately 1930- to 4760-fold higher than extracellular concentrations.
Our study is the first to quantitatively measure the significant uptake
of polymyxin in renal tubular cells and provides crucial information
for the understanding of polymyxin-induced nephrotoxicity. Importantly,
our approach represents a significant methodological advancement in
determination of drug uptake for single-cell pharmacology.
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