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ABSTRACT: Purpose
Currently, the most commonly used chelator for labelling antibodies with 89Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the 89Zr-DFO complex results in release of 89Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the 89Zr radiometal. The aim was to compare the in vitro and in vivo stability of [89Zr]Zr-DFOcyclo*, [89Zr]Zr-DFO* and [89Zr]Zr-DFO.Methods
The stability of 89Zr-labelled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The immunoreactive fraction, IC50, and internalization rate of the conjugates were evaluated using HER2-expressing SKOV-3 cells. The in vivo distribution was investigated in mice with subcutaneous HER2+ SKOV-3 or HER2- MDA-MB-231 xenografts by PET/CT imaging and quantitative ex vivo tissue analyses 7 days after injection.Results
89Zr-labelled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In competition with excess DFO, DFOcyclo*-trastuzumab was significantly more stable than the corresponding DFO and DFO* conjugates (p?+ SKOV-3 tumour-bearing mice showed significantly lower bone uptake (p?89Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5?±?0.3%ID/g, knee 2.1?±?0.4%ID/g) or [89Zr]Zr-DFO*-trastuzumab (femur 2.0?±?0.3%ID/g, knee 2.68?±?0.4%ID/g) than after injection with [89Zr]Zr-DFO-trastuzumab (femur 4.5?±?0.6%ID/g, knee 7.8?±?0.6%ID/g). Blood levels, tumour uptake and uptake in other organs were not significantly different at 168 h after injection. HER2- MDA-MB-231 tumour-bearing mice showed significantly lower tumour uptake (p?89Zr]Zr-DFOcyclo*-trastuzumab (16.2?±?10.1%ID/g) and [89Zr]Zr-DFO-trastuzumab (19.6?±?3.2%ID/g) than HER2+ SKOV-3 tumour-bearing mice (72.1?±?14.6%ID/g and 93.1?±?20.9%ID/g, respectively), while bone uptake was similar.Conclusion
89Zr-labelled DFOcyclo* and DFOcyclo*-trastuzumab showed higher in vitro and in vivo stability than the current commonly used 89Zr-DFO-trastuzumab. DFOcyclo* is a promising candidate to become the new clinically used standard chelator for 89Zr immunoPET.
SUBMITTER: Raave R
PROVIDER: S-EPMC6647232 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
European journal of nuclear medicine and molecular imaging 20190603 9
<h4>Purpose</h4>Currently, the most commonly used chelator for labelling antibodies with <sup>89</sup>Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the <sup>89</sup>Zr-DFO complex results in release of <sup>89</sup>Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the <sup>89</sup>Zr radiometal. The aim was to compare ...[more]