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Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging.

Petrik M, Franssen GM, Haas H, Laverman P, Hörtnagl C, Schrettl M, Helbok A, Lass-Flörl C, Decristoforo C - Eur. J. Nucl. Med. Mol. Imaging (2012)

Bottom Line: In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus.In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability.In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images. (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus.

View Article: PubMed Central - PubMed

Affiliation: Clinical Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria. milospetrik@seznam.cz

ABSTRACT

Purpose: Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with (68)Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising (68)Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).

Methods: Siderophores were labelled with (68)Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic μPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo.

Results: (68)Ga-siderophores were labelled with high radiochemical purity and specific activity. (68)Ga-TAFC and (68)Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images.

Conclusion: (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging.

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Specific uptake (difference between the uptake in iron-deficient and iron-sufficient cultures) of 68Ga-TAFC and 68Ga-FOXE by A. fumigatus over time (a) and 45 min after incubation blocked with excess of ferri-siderophore and/or sodium azide (b)
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Fig2: Specific uptake (difference between the uptake in iron-deficient and iron-sufficient cultures) of 68Ga-TAFC and 68Ga-FOXE by A. fumigatus over time (a) and 45 min after incubation blocked with excess of ferri-siderophore and/or sodium azide (b)

Mentions: Uptake of 68Ga-TAFC and 68Ga-FOXE was highly dependent on the mycelial iron load. Both compounds showed rapid uptake by A. fumigatus in iron-deficient cultures, which could be blocked with excess of ferri-siderophore and/or sodium azide and was significantly lower (P < 0.05) in iron-sufficient media. Figure 2 shows 68Ga-TAFC and 68Ga-FOXE specific uptake over time (Fig. 2a) and specific uptake 45 min after incubation (Fig. 2b), which could be blocked with excess of ferri-siderophore and/or sodium azide in the A. fumigatus cultures.Fig. 2


Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging.

Petrik M, Franssen GM, Haas H, Laverman P, Hörtnagl C, Schrettl M, Helbok A, Lass-Flörl C, Decristoforo C - Eur. J. Nucl. Med. Mol. Imaging (2012)

Specific uptake (difference between the uptake in iron-deficient and iron-sufficient cultures) of 68Ga-TAFC and 68Ga-FOXE by A. fumigatus over time (a) and 45 min after incubation blocked with excess of ferri-siderophore and/or sodium azide (b)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369139&req=5

Fig2: Specific uptake (difference between the uptake in iron-deficient and iron-sufficient cultures) of 68Ga-TAFC and 68Ga-FOXE by A. fumigatus over time (a) and 45 min after incubation blocked with excess of ferri-siderophore and/or sodium azide (b)
Mentions: Uptake of 68Ga-TAFC and 68Ga-FOXE was highly dependent on the mycelial iron load. Both compounds showed rapid uptake by A. fumigatus in iron-deficient cultures, which could be blocked with excess of ferri-siderophore and/or sodium azide and was significantly lower (P < 0.05) in iron-sufficient media. Figure 2 shows 68Ga-TAFC and 68Ga-FOXE specific uptake over time (Fig. 2a) and specific uptake 45 min after incubation (Fig. 2b), which could be blocked with excess of ferri-siderophore and/or sodium azide in the A. fumigatus cultures.Fig. 2

Bottom Line: In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus.In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability.In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images. (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus.

View Article: PubMed Central - PubMed

Affiliation: Clinical Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria. milospetrik@seznam.cz

ABSTRACT

Purpose: Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with (68)Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising (68)Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).

Methods: Siderophores were labelled with (68)Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic μPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo.

Results: (68)Ga-siderophores were labelled with high radiochemical purity and specific activity. (68)Ga-TAFC and (68)Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images.

Conclusion: (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging.

Show MeSH
Related in: MedlinePlus