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

Abstract

PurposeInvasive 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 68Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising 68Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).MethodsSiderophores were labelled with 68Ga 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.Results68Ga-siderophores were labelled with high radiochemical purity and specific activity. 68Ga-TAFC and 68Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, 68Ga-TAFC and 68Ga-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.Conclusion68Ga-TAFC and 68Ga-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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-012-2110-3) contains supplementary material, which is available to authorized users.

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

“…Siderophore biosynthetic enzymes are also upregulated in conidia internalized by airway epithelial cells (Oosthuizen et al, 2011). Aspergillus fumigatus has been reported to utilize xenosiderophores including ferrichrome, coprogen, ferrioxamine B and ferrioxamine E (Petrik et al, 2012). Candida albicans, also a frequent colonizer in CF (Chotirmall et al, 2010), has been reported to produce both hydroxamateand phenolate-type siderophores (Holzberg & Artis, 1983;Ismail et al, 1985); however, siderophore biosynthesis genes have not been identified in the Candida albicans genome (Haas, 2003).…”

Longitudinal, in vivo assessment of invasive pulmonary aspergillosis in mice by computed tomography and magnetic resonance imaging

“…20 Nuclear imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), have also been used for detecting pulmonary aspergillosis in rodents by using radioactive probes. 21,22 As the use of radioactive tracers requires their production in cyclotrons, PET and SPECT may not always be the most practical methods for a preclinical setting. Also, the selectivity of PET tracers, such as 68 Ga-siderophores and 89 Zr-oxalate, for detecting Aspergillus infections has yet to be investigated in more detail.…”

“…Also, the selectivity of PET tracers, such as 68 Ga-siderophores and 89 Zr-oxalate, for detecting Aspergillus infections has yet to be investigated in more detail. 21,23 Computed tomography (CT) is highly suitable for lung applications because it produces high-resolution 3D images (o100 μm) with an excellent air-tissue contrast. 24,25 The value of this imaging technique has been studied in disease models of lung fibrosis, lung emphysema and lung neoplasms.…”

Biotechnology of siderophores in high-impact scientific fields

“…Petrik and colleagues demonstrated clinical use in imaging pulmonary aspergillosis (89). Mouse and rat infection models were developed and siderophores (triacetylfusarinine and ferrioxamine E) were labeled with gallium 68 ( 68 Ga).…”