“[89Zr] siderophores could be applied for longitudinal PET studies of fungal infections”
Iron is an essential nutrient for all cells, being required for respiration and the synthesis of DNA. Although it is the most abundant element in the earth’s crust, the low solubility of iron can limit its availability.
Mammals have overcome this problem using proteins that bind iron, e.g., hemoglobin. Most microorganisms, however, require a constant supply of iron. They achieve this by excreting siderophores, high affinity, iron-selective chelators, into the extracellular environment. Once the siderophore has sequestered and solubilized the external iron, it is actively transported back into the cell so the iron can be utilized for intracellular metabolic processes.
When iron levels are low, expression of the genes encoding siderophores is increased. Some species also produce specialized siderophores that remain within the cell to provide an iron reserve. The particular siderophore used is generally specific to a given microorganism. Several pathogenic bacteria and fungi use siderophore-iron complexes as a means of survival in host animal tissue.
As a consequence of being amongst the strongest known binders of iron and their prevalence amongst invading pathogens, siderophores and their analogues are used for a wide range of medical applications, e.g., selective drug delivery; treatment of thalassemia, malaria and sickle cell disease.
More recently, a range of siderophores labelled with Gallium-68 (Ga-68) has been developed for use as specific agents for molecular imaging using positron emission tomography (PET). Since Ga-68 is of similar size and structure to the Fe3+ ion, the labelled siderophore complex is transported inside the microbial cell of interest. In this way the extent of an infection can be assessed through PET imaging. However, Ga-68 has a short half-life that limits the time over which imaging is possible. Consequently, siderophores labelled with Zirconium-89 (Zr-89), which has a much longer half-life, have been produced.
In vivo and in vitro properties have recently been compared between siderophores labelled with Zr-89 and the respective Ga-68 siderophore complexes to explore whether the extra charge on the Zr-89 affects the stability or other properties of the siderophore complex.
The respective in vitro partition coefficients, in vitro stability and protein binding affinities were determined for four siderophores (both Zr-89 and Ga-68 complexes): triacetylfusarinine, ferrioxamine E, ferrioxamine B and ferrichrome A. Each radiolabeled siderophore was also injected into an 8-week old female Balb/c mice.
PET and computed tomography images were acquired during the 90 minutes after injection using a Bruker Albira PET/SPECT/CT small animal imaging system. The amount of radioactivity in different organ samples was measured in an automatic gamma counter.
The Zr-89 and Ga-68 siderophore complexes demonstrated comparable behaviors both in vitro and in vivo. Zr-89-labelled siderophores could therefore provide an alternative to Ga-68 siderophores, allowing longitudinal PET studies of fungal infections.