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The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent.

ABSTRACT: The opportunistic pathogen Pseudomonas aeruginosa causes infections that are difficult to treat by antibiotic therapy. This bacterium can cause biofilm infections where it shows tolerance to antibiotics. Here we report the novel use of a metallo-complex, desferrioxamine-gallium (DFO-Ga) that targets P. aeruginosa iron metabolism. This complex kills free-living bacteria and blocks biofilm formation. A combination of DFO-Ga and the anti-Pseudomonas antibiotic gentamicin caused massive killing of P. aeruginosa cells in mature biofilms. In a P. aeruginosa rabbit corneal infection, topical administration of DFO-Ga together with gentamicin decreased both infiltrate and final scar size by about 50% compared to topical application of gentamicin alone. The use of DFO-Ga as a Trojan horse delivery system that interferes with iron metabolism shows promise as a treatment for P. aeruginosa infections.

SUBMITTER: Banin E

PROVIDER: S-EPMC2575493 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent.

Banin Ehud E Lozinski Alina A Brady Keith M KM Berenshtein Eduard E Butterfield Phillip W PW Moshe Maya M Chevion Mordechai M Greenberg Everett Peter EP Banin Eyal E

Proceedings of the National Academy of Sciences of the United States of America 20081017 43

The opportunistic pathogen Pseudomonas aeruginosa causes infections that are difficult to treat by antibiotic therapy. This bacterium can cause biofilm infections where it shows tolerance to antibiotics. Here we report the novel use of a metallo-complex, desferrioxamine-gallium (DFO-Ga) that targets P. aeruginosa iron metabolism. This complex kills free-living bacteria and blocks biofilm formation. A combination of DFO-Ga and the anti-Pseudomonas antibiotic gentamicin caused massive killing of P ...[more]

PMID: 18931304

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Project description:IntroductionRadiolabeled exendin-4 (Ex4) derivatives are used to target the glucagon-like peptide-1 receptor (GLP-1R) for the clinical diagnosis of insulinomas, a rare type of neuroendocrine tumor. Gallium-68 is an ideal diagnostic nuclide for this application and a study evaluating an exendin-4-NODAGA conjugate is currently underway. However, in complexion with the chelator DFO, its in vivo stability has been a matter of dispute. The aim of this work was to directly compare [68Ga]Ga-Ex4NOD with [68Ga]Ga-Ex4DFO in vitro and in vivo.MethodsIn our approach, we directly compared N'-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]-N-hydroxy-butane diamide (desferriox-amine B, DFO) and 2-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) pentanedioic acid (NODAGA) conjugated to exendin-4 in vitro and in vivo. We radiolabeled the peptides with gallium-68, followed by HPLC quality control. In vitro characterization was performed in CHL cells overexpressing the GLP-1R and in vivo studies were conducted with CD1 nu/nu mice carrying tumors derived from these cells.ResultsWe found that both peptides could be radiolabeled with a molar activity of about 9.33 MBq/nmol without further purification. They internalized equally well into GLP-1R-expressing cells and their IC50 was similar with 15.6 ± 7.8 nM and 18.4 ± 3.0 nM for [natGa]Ga-Ex4NOD and [natGa]Ga-Ex4DFO, respectively. In vivo, [68Ga]Ga-Ex4NOD accumulated more in all tissue, while [68Ga]Ga-Ex4DFO exhibited a more favorable target-to-kidney ratio.Conclusion and relevanceDFO is a suitable chelator for the radiolabeling of exendin-4 derivatives with gallium-68 for in vitro and preclinical in vivo studies. DFO performed better in vivo due to its significantly lower kidney accumulation (p < 0.0001). It was also found to be stable in vivo in mice, contrary to earlier reports. Based on our results, the DFO chelating system in combination with exendin-4 would be an interesting option for clinical imaging of insulinomas.

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The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent.

Publications

The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent.

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