Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89 Zr-immunoPET - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue European Journal of Nuclear Medicine and Molecular Imaging Année : 2019

Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89 Zr-immunoPET

Résumé

Purpose Currently, the most commonly used chelator for labelling antibodies with 89 Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the 89 Zr-DFO complex results in release of 89 Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the 89 Zr radiometal. The aim was to compare the in vitro and in vivo stability of [ 89 Zr]Zr-DFOcyclo*, [ 89 Zr]Zr-DFO* and [ 89 Zr]Zr-DFO. Methods The stability of 89 Zr-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, IC 50 , 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 89 Zr-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 < 0.001). Cell binding and internalization were similar for the three conjugates. In in vivo studies, HER2 + SKOV-3 tumour-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [ 89 Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [ 89 Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [ 89 Zr]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 < 0.001) after injection with [ 89 Zr]Zr-DFOcyclo*-trastuzumab (16.2 ± 10.1%ID/g) and [ 89 Zr]Zr-DFO-trastuzumab (19.6 ± 3.2%ID/g) than HER2 + SKOV-3 tumour-bearing mice (72.
Fichier principal
Vignette du fichier
Publi059.pdf (1.94 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Loading...

Dates et versions

hal-02343550 , version 1 (02-11-2019)

Identifiants

Citer

René Raavé, Gerwin Sandker, Pierre Adumeau, Christian Borch Jacobsen, Floriane Mangin, et al.. Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89 Zr-immunoPET. European Journal of Nuclear Medicine and Molecular Imaging, 2019, 46 (9), pp.1966 - 1977. ⟨10.1007/s00259-019-04343-2⟩. ⟨hal-02343550⟩
111 Consultations
127 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More