TY - JOUR

T1 - The impact of weakly bound (89)Zr on preclinical studies

T2 - Non-specific accumulation in solid tumors and aspergillus infection

AU - Severin, Gregory W

AU - Jørgensen, Jesper Tranekjær

AU - Wiehr, Stefan

AU - Rolle, Anna-Maria

AU - Hansen, Anders E

AU - Maurer, Andreas

AU - Hasenberg, Mike

AU - Pichler, Bernd

AU - Kjær, Andreas

AU - Jensen, Andreas I

N1 - Copyright © 2014 Elsevier Inc. All rights reserved.

PY - 2015/4

Y1 - 2015/4

N2 - Preclinical studies involving (89)Zr often report significant bone accumulation, which is associated with dissociation of the radiometal from the tracer. However, experiments determining the uptake of unbound (89)Zr in disease models are not performed as routine controls. The purpose of the present study was to investigate the impact of free or weakly bound (89)Zr on PET quantifications in disease models, in order to determine if such control experiments are warranted.METHODS: Chemical studies were carried out to find a (89)Zr compound that would solubilize the (89)Zr as a weak chelate, thus mimicking free or weakly bound (89)Zr released in circulation. (89)Zr oxalate had the desired characteristics, and was injected into mice bearing FaDu and HT29 solid tumor xenografts, and mice infected in the lungs with the mold Aspergillus fumigatus, as well as in healthy controls (naïve). PET/CT or PET/MR imaging followed to quantify the distribution of the radionuclide in the disease models.RESULTS: (89)Zr oxalate was found to have a plasma half-life of 5.1±2.3h, accumulating mainly in the bones of all animals. Both tumor types accumulated (89)Zr on the order of 2-4 %ID/cm(3), which is comparable to EPR-mediated accumulation of certain species. In the aspergillosis model, the concentration of (89)Zr in lung tissue of the naïve animals was 6.0±1.1 %ID/g. This was significantly different from that of the animals with advanced disease, showing 11.6% ±1.8 %ID/g.CONCLUSIONS: Given the high levels of (89)Zr accumulation in the disease sites in the present study, we recommend control experiments mapping the biodistribution of free (89)Zr in any preclinical study employing (89)Zr where bone uptake is observed. Aqueous (89)Zr oxalate appears to be a suitable compound for such studies. This is especially relevant in studies where the tracer accumulation is based upon passive targeting, such as EPR.

AB - Preclinical studies involving (89)Zr often report significant bone accumulation, which is associated with dissociation of the radiometal from the tracer. However, experiments determining the uptake of unbound (89)Zr in disease models are not performed as routine controls. The purpose of the present study was to investigate the impact of free or weakly bound (89)Zr on PET quantifications in disease models, in order to determine if such control experiments are warranted.METHODS: Chemical studies were carried out to find a (89)Zr compound that would solubilize the (89)Zr as a weak chelate, thus mimicking free or weakly bound (89)Zr released in circulation. (89)Zr oxalate had the desired characteristics, and was injected into mice bearing FaDu and HT29 solid tumor xenografts, and mice infected in the lungs with the mold Aspergillus fumigatus, as well as in healthy controls (naïve). PET/CT or PET/MR imaging followed to quantify the distribution of the radionuclide in the disease models.RESULTS: (89)Zr oxalate was found to have a plasma half-life of 5.1±2.3h, accumulating mainly in the bones of all animals. Both tumor types accumulated (89)Zr on the order of 2-4 %ID/cm(3), which is comparable to EPR-mediated accumulation of certain species. In the aspergillosis model, the concentration of (89)Zr in lung tissue of the naïve animals was 6.0±1.1 %ID/g. This was significantly different from that of the animals with advanced disease, showing 11.6% ±1.8 %ID/g.CONCLUSIONS: Given the high levels of (89)Zr accumulation in the disease sites in the present study, we recommend control experiments mapping the biodistribution of free (89)Zr in any preclinical study employing (89)Zr where bone uptake is observed. Aqueous (89)Zr oxalate appears to be a suitable compound for such studies. This is especially relevant in studies where the tracer accumulation is based upon passive targeting, such as EPR.

U2 - 10.1016/j.nucmedbio.2014.11.005

DO - 10.1016/j.nucmedbio.2014.11.005

M3 - Journal article

C2 - 25583221

VL - 42

SP - 360

EP - 368

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

SN - 0969-8051

IS - 4

ER -