Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.

Varache, M.; Rizzo, S.; Sayers, E. J.; Newbury, L.; Mason, A.; Liao, C.-T.; Chiron, E.; Bourdiec, N.; Jones, A.; Fraser, D. J.; Taylor, P. R.; Jones, A. T.; Thomas, D. W.; Ferguson, E. L.

doi:10.1101/2023.11.02.565265

bioRxiv · 10.1101/2023.11.02.565265

Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.

Varache, M.·Rizzo, S.·Sayers, E. J.·Newbury, L.·Mason, A.·Liao, C.-T.·Chiron, E.·Bourdiec, N.·Jones, A.·Fraser, D. J.·Taylor, P. R.·Jones, A. T.·Thomas, D. W.·Ferguson, E. L.

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Abstract

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected /inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo. We discovered that dextrin conjugation effectively reduced colistins toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistins renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/565265v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1ec6ac8org.highwire.dtl.DTLVardef@56a2b1org.highwire.dtl.DTLVardef@1d347fborg.highwire.dtl.DTLVardef@1ab7da_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Varache, M., Rizzo, S., Sayers, E. J., Newbury, L., Mason, A., Liao, C.-T., Chiron, E., Bourdiec, N., Jones, A., Fraser, D. J., Taylor, P. R., Jones, A. T., Thomas, D. W., Ferguson, E. L.. 2023-11-04. Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.. https://doi.org/10.1101/2023.11.02.565265

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