肾毒性
化学
多粘菌素
多粘菌素B
肾
药理学
荧光显微镜
抗生素
生物化学
荧光
毒性
内科学
医学
量子力学
物理
有机化学
作者
Mohammad Azad Malik,Kade D. Roberts,Heidi H. Yu,Boyin Liu,Alice V. Schofield,Simon James,Daryl L. Howard,Roger L. Nation,Kelly L. Rogers,Martin D. de Jonge,Philip E. Thompson,Jing Fu,Tony Velkov,Jian Li
摘要
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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