Deferoxamine as a chelator for 67Ga in the preparation of antibody conjugates

Govindan, Serengulam V.; Michel, Rosana B.; Griffiths, Gary L.; Goldenberg, David M.; Mattes, M. Jules

doi:10.1016/j.nucmedbio.2005.04.009

Cited by 30 publications

(23 citation statements)

References 15 publications

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“…Some controversy exists about the conditional stability constant of the Ga-Df complex at neutral pH. The in vitro stability we found corresponds well with the earlier findings of Smith-Jones et al [25], Fani et al [27] and Furukawa et al [24], but seems to be rather in contrast with the findings of Caraco et al [42] and Govindan et al [26]. We feel that this is only an apparent controversy because the conditions under which Caraco et al produced their Ga-Df complex are completely different.…”

Section: Discussionsupporting

confidence: 87%

Facile labelling of an anti-epidermal growth factor receptor Nanobody with 68Ga via a novel bifunctional desferal chelate for immuno-PET

Vosjan

Perk

Roovers

et al. 2011

Eur J Nucl Med Mol Imaging

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PurposeThe ∼15 kDa variable domains of camelid heavy-chain-only antibodies (called Nanobodies®) have the flexibility to be formatted as monovalent, monospecific, multivalent or multispecific single chain proteins with either fast or slow pharmacokinetics. We report the evaluation of the fast kinetic anti-epidermal growth factor receptor (EGFR) Nanobody 7D12, labelled with 68Ga via the novel bifunctional chelate (BFC) p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS). Df-Bz-NCS has recently been introduced as the chelate of choice for 89Zr immuno-positron emission tomography (PET).MethodsNanobody 7D12 was premodified with Df-Bz-NCS at pH 9. Radiolabelling with purified 68Ga was performed at pH 5.0–6.5 for 5 min at room temperature. For in vitro stability measurements in storage buffer (0.25 M NaOAc with 5 mg ml−1 gentisic acid, pH 5.5) at 4°C or in human serum at 37°C, a mixture of 67Ga and 68Ga was used. Biodistribution and immuno-PET studies of 68Ga-Df-Bz-NCS-7D12 were performed in nude mice bearing A431 xenografts using 89Zr-Df-Bz-NCS-7D12 as the reference conjugate.ResultsThe Df-Bz-NCS chelate was conjugated to Nanobody 7D12 with a chelate to Nanobody molar substitution ratio of 0.2:1. The overall 68Ga radiochemical yield was 55–70% (not corrected for decay); specific activity was 100–500 MBq/mg. Radiochemical purity of the conjugate was >96%, while the integrity and immunoreactivity were preserved. 68/67Ga-Df-Bz-NCS-7D12 was stable in storage buffer as well as in human serum during a 5-h incubation period (<2% radioactivity loss). In biodistribution studies the 68Ga-labelled Nanobody 7D12 showed high uptake in A431 tumours (ranging from 6.1 ± 1.3 to 7.2 ± 1.5%ID/g at 1–3 h after injection) and high tumour to blood ratios, which increased from 8.2 to 14.4 and 25.7 at 1, 2 and 3 h after injection, respectively. High uptake was also observed in the kidneys. Biodistribution was similar to that of the reference conjugate 89Zr-Df-Bz-NCS-7D12. Tumours were clearly visualized in a PET imaging study.ConclusionVia a rapid procedure under mild conditions a 68Ga-Nanobody was obtained that exhibited high tumour uptake and tumour to normal tissue ratios in nude mice bearing A431 xenografts. Fast kinetic 68Ga-Nanobody conjugates can be promising tools for tumour detection and imaging of target expression.

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Section: Discussionsupporting

confidence: 87%

Facile labelling of an anti-epidermal growth factor receptor Nanobody with 68Ga via a novel bifunctional desferal chelate for immuno-PET

Vosjan

Perk

Roovers

et al. 2011

Eur J Nucl Med Mol Imaging

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“…Eventually, we were successful in radiolabeling NOTA-MNT in >90% yield as a heterogeneous mixture at pH 5.0 with subsequent solubilization by buffer/DMSO solution. The maximum specific activity achieved (2.0 Ci/μmol, ~26 mCi/mg) was comparable [24] or even higher [27] to those reported elsewhere. The observed plateau of specific activity might be due to the limited number of chelators present in the MNT.…”

Section: Discussionsupporting

confidence: 82%

“…The therapeutic potential of several 67 Ga-labeled compounds has been described [2, 27, 32–34]; however, comparison to those reported herein must be done with caution because differences in factors such as cell sensitivity, geometry, assay design and stability of the labeled agent could complicate interpretation. Nonetheless, the calculated radiation absorbed doses of 67 Ga-NOTA-MNT required to reduce survival to 37% and 10%, 8 and 18 Gy, respectively, were in good agreement to those reported previously for several internalizing antibodies labeled with 67 Ga [33–35].…”

Section: Discussionmentioning

confidence: 97%

Radiolabeling and in vitro evaluation of 67Ga-NOTA-modular nanotransporter – A potential Auger electron emitting EGFR-targeted radiotherapeutic

Koumarianou

Slastnikova

Pruszyński

et al. 2014

Nuclear Medicine and Biology

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Introduction Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with 67Ga. Methods EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with 67Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5–5.5) of 67Ga. Cellular and nuclei uptake of 67Ga-NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of 67Ga-EDTA, 67Ga-NOTA-BSA and 67Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed. Results 67Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6 mCi/mg. The in vitro kinetics revealed an increased uptake over 24 h. 55% of the internalized radioactivity was detected in the nuclei at 1 h. The cytotoxicity of 67Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific 67Ga-NOTA-BSA and 67Ga-EDTA. While its cytotoxic potency was 13 and 72 – fold higher when compared to 67Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 9 Gy, confirms the high specific index of 67Ga. Conclusion These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters.

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“…DFO as bifunctional chelator for antibodies was also proposed for radiotherapeutic applications using 67 Ga Auger electrons. Govindan et al [73] prepared different DFO-antibody conjugates and reported two main problems limiting further development. First, the stability was inadequate for the 3-day half-life of the nuclide.…”

Section: Desferrioxamine and Galliummentioning

confidence: 99%

Siderophores for molecular imaging applications

Petřík

Zhai

Haas

et al. 2016

Clin Transl Imaging

106

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This review covers publications on siderophores applied for molecular imaging applications, mainly for radionuclide-based imaging. Siderophores are low molecular weight chelators produced by bacteria and fungi to scavenge essential iron. Research on these molecules has a continuing history over the past 50 years. Many biomedical applications have been developed, most prominently the use of the siderophore desferrioxamine (DFO) to tackle iron overload related diseases. Recent research described the upregulation of siderophore production and transport systems during infection. Replacing iron in siderophores by radionuclides, the most prominent Ga-68 for PET, opens approaches for targeted imaging of infection; the proof of principle has been reported for fungal infections using 68 Ga-triacetylfusarinine C (TAFC). Additionally, fluorescent siderophores and therapeutic conjugates have been described and may be translated to optical imaging and theranostic applications. Siderophores have also been applied as bifunctional chelators, initially DFO as chelator for Ga-67 and more recently for Zr-89 where it has become the standard chelator in Immuno-PET. Improved DFO constructs and bifunctional chelators based on cyclic siderophores have recently been developed for Ga-68 and Zr-89 and show promising properties for radiopharmaceutical development in PET. A huge potential from basic biomedical research on siderophores still awaits to be utilized for clinical and translational imaging.

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Deferoxamine as a chelator for 67Ga in the preparation of antibody conjugates

Cited by 30 publications

References 15 publications

Facile labelling of an anti-epidermal growth factor receptor Nanobody with 68Ga via a novel bifunctional desferal chelate for immuno-PET

Facile labelling of an anti-epidermal growth factor receptor Nanobody with 68Ga via a novel bifunctional desferal chelate for immuno-PET

Radiolabeling and in vitro evaluation of 67Ga-NOTA-modular nanotransporter – A potential Auger electron emitting EGFR-targeted radiotherapeutic

Siderophores for molecular imaging applications

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