Significant accumulation of polymyxin in single renal tubular cells: a medicinal chemistry and triple correlative microscopy approach

Mohammad Abul Kalam Azad, Kade Douglas Roberts, Heidi Yu, Boyin Liu, Alice V Schofield, Simon Alexander James, Daryl L Howard, Roger Leigh Nation, Kelly Lee Rogers, Martin Daly de Jonge, Philip Thompson, Jing Fu, Tony Velkov, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1590 - 1595
Number of pages6
JournalAnalytical Chemistry
Volume87
Issue number3
DOIs
Publication statusPublished - 2015

Cite this