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Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection
PURPOSE: Aspergillus fumigatus produces the siderophore triacetylfusarinine C (TAFC) for iron acquisition which is essential for its virulence. Therefore, TAFC is a specific marker for invasive aspergillosis. We have shown previously that positron emission tomography (PET) imaging with [(68)Ga]TAFC...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877352/ https://www.ncbi.nlm.nih.gov/pubmed/30838551 http://dx.doi.org/10.1007/s11307-019-01325-6 |
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author | Kaeopookum, Piriya Summer, Dominik Pfister, Joachim Orasch, Thomas Lechner, Beatrix E. Petrik, Milos Novy, Zbynek Matuszczak, Barbara Rangger, Christine Haas, Hubertus Decristoforo, Clemens |
author_facet | Kaeopookum, Piriya Summer, Dominik Pfister, Joachim Orasch, Thomas Lechner, Beatrix E. Petrik, Milos Novy, Zbynek Matuszczak, Barbara Rangger, Christine Haas, Hubertus Decristoforo, Clemens |
author_sort | Kaeopookum, Piriya |
collection | PubMed |
description | PURPOSE: Aspergillus fumigatus produces the siderophore triacetylfusarinine C (TAFC) for iron acquisition which is essential for its virulence. Therefore, TAFC is a specific marker for invasive aspergillosis. We have shown previously that positron emission tomography (PET) imaging with [(68)Ga]TAFC exhibited excellent targeting properties in an A. fumigatus rat infection model. In this study, we aimed to prepare TAFC analogs modifying fusarinine C (FSC) by acylation with different carbon chain lengths as well as with charged substituents and investigated the influence of introduced substituents on preservation of TAFC characteristics in vitro and in vivo. PROCEDURES: Fifteen TAFC derivatives were prepared and labeled with gallium-68. In vitro uptake assays were carried out in A. fumigatus under iron-replete as well as iron-depleted conditions and distribution coefficient was determined. Based on these assays, three compounds, [(68)Ga]tripropanoyl(FSC) ([(68)Ga]TPFC), [(68)Ga]diacetylbutanoyl(FSC) ([(68)Ga]DABuFC), and [(68)Ga]trisuccinyl(FSC) ([(68)Ga]FSC(suc)(3)), with high, medium, and low in vitro uptake in fungal cultures, were selected for further evaluation. Stability and protein binding were evaluated and in vivo imaging performed in the A. fumigatus rat infection model. RESULTS: In vitro uptake studies using A. fumigatus revealed specific uptake of mono- and trisubstituted TAFC derivatives at RT. Lipophilicities as expressed by logD were 0.34 to − 3.80. The selected compounds displayed low protein binding and were stable in PBS and serum. Biodistribution and image contrast in PET/X-ray computed tomography of [(68)Ga]TPFC and [(68)Ga]DABuFC were comparable to [(68)Ga]TAFC, whereas no uptake in the infected region was observed with [(68)Ga]FSC(suc)(3). CONCLUSIONS: Our studies show the possibility to modify TAFC without losing its properties and specific recognition by A. fumigatus. This opens also new ways for multimodality imaging or theranostics of fungal infection by introducing functionalities such as fluorescent dyes or antifungal moieties. |
format | Online Article Text |
id | pubmed-6877352 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
spelling | pubmed-68773522020-03-01 Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection Kaeopookum, Piriya Summer, Dominik Pfister, Joachim Orasch, Thomas Lechner, Beatrix E. Petrik, Milos Novy, Zbynek Matuszczak, Barbara Rangger, Christine Haas, Hubertus Decristoforo, Clemens Mol Imaging Biol Article PURPOSE: Aspergillus fumigatus produces the siderophore triacetylfusarinine C (TAFC) for iron acquisition which is essential for its virulence. Therefore, TAFC is a specific marker for invasive aspergillosis. We have shown previously that positron emission tomography (PET) imaging with [(68)Ga]TAFC exhibited excellent targeting properties in an A. fumigatus rat infection model. In this study, we aimed to prepare TAFC analogs modifying fusarinine C (FSC) by acylation with different carbon chain lengths as well as with charged substituents and investigated the influence of introduced substituents on preservation of TAFC characteristics in vitro and in vivo. PROCEDURES: Fifteen TAFC derivatives were prepared and labeled with gallium-68. In vitro uptake assays were carried out in A. fumigatus under iron-replete as well as iron-depleted conditions and distribution coefficient was determined. Based on these assays, three compounds, [(68)Ga]tripropanoyl(FSC) ([(68)Ga]TPFC), [(68)Ga]diacetylbutanoyl(FSC) ([(68)Ga]DABuFC), and [(68)Ga]trisuccinyl(FSC) ([(68)Ga]FSC(suc)(3)), with high, medium, and low in vitro uptake in fungal cultures, were selected for further evaluation. Stability and protein binding were evaluated and in vivo imaging performed in the A. fumigatus rat infection model. RESULTS: In vitro uptake studies using A. fumigatus revealed specific uptake of mono- and trisubstituted TAFC derivatives at RT. Lipophilicities as expressed by logD were 0.34 to − 3.80. The selected compounds displayed low protein binding and were stable in PBS and serum. Biodistribution and image contrast in PET/X-ray computed tomography of [(68)Ga]TPFC and [(68)Ga]DABuFC were comparable to [(68)Ga]TAFC, whereas no uptake in the infected region was observed with [(68)Ga]FSC(suc)(3). CONCLUSIONS: Our studies show the possibility to modify TAFC without losing its properties and specific recognition by A. fumigatus. This opens also new ways for multimodality imaging or theranostics of fungal infection by introducing functionalities such as fluorescent dyes or antifungal moieties. 2019-12 /pmc/articles/PMC6877352/ /pubmed/30838551 http://dx.doi.org/10.1007/s11307-019-01325-6 Text en http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Article Kaeopookum, Piriya Summer, Dominik Pfister, Joachim Orasch, Thomas Lechner, Beatrix E. Petrik, Milos Novy, Zbynek Matuszczak, Barbara Rangger, Christine Haas, Hubertus Decristoforo, Clemens Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection |
title | Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection |
title_full | Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection |
title_fullStr | Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection |
title_full_unstemmed | Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection |
title_short | Modifying the Siderophore Triacetylfusarinine C for Molecular Imaging of Fungal Infection |
title_sort | modifying the siderophore triacetylfusarinine c for molecular imaging of fungal infection |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877352/ https://www.ncbi.nlm.nih.gov/pubmed/30838551 http://dx.doi.org/10.1007/s11307-019-01325-6 |
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