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European Journal of Nuclear Medicine and Molecular Imaging

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01-03-2012 | Original Article

Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with ¹¹¹In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts

Authors: Jennie Malmberg, Anna Perols, Zohreh Varasteh, Mohamed Altai, Alexis Braun, Mattias Sandström, Ulrike Garske, Vladimir Tolmachev, Anna Orlova, Amelie Eriksson Karlström

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2012

Abstract

Purpose

In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer.

Methods

A synthetic variant of the anti-HER2 Z_HER2:342 Affibody molecule, Z_HER2:S1, was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with ¹¹¹In, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts.

Results

The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-Z_HER2:S1, NOTA-Z_HER2:S1 and NODAGA-Z_HER2:S1, respectively. A comparative study of ¹¹¹In-labelled DOTA-Z_HER2:S1, NOTA-Z_HER2:S1 and NODAGA-Z_HER2:S1 in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. ¹¹¹In-NODAGA-Z_HER2:S1 had the most rapid clearance from blood and healthy tissues. ¹¹¹In-NOTA-Z_HER2:S1 showed high hepatic uptake and was excluded from further evaluation. ¹¹¹In-DOTA-Z_HER2:S1 and ¹¹¹In-NODAGA-Z_HER2:S1 demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of ¹¹¹In-NODAGA-Z_HER2:S1, 5.6 ± 0.4%ID/g, was significantly lower than the uptake of ¹¹¹In-DOTA-Z_HER2:S1, 7.4 ± 0.5%ID/g, presumably because of lower bioavailability due to more rapid clearance. ¹¹¹In-NODAGA-Z_HER2:S1 provided higher tumour-to-blood ratio, but somewhat lower tumour-to-liver, tumour-to-spleen and tumour-to-bone ratios.

Conclusion

Since distant prostate cancer metastases are situated in bone or bone marrow, the higher tumour-to-bone ratio is the most important. This renders ¹¹¹In-DOTA-Z_HER2:S1 a preferable agent for imaging of HER2 expression in disseminated prostate cancer.

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Title: Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with 111In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts
Authors: Jennie Malmberg
Anna Perols
Zohreh Varasteh
Mohamed Altai
Alexis Braun
Mattias Sandström
Ulrike Garske
Vladimir Tolmachev
Anna Orlova
Amelie Eriksson Karlström
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2012
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-011-1992-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with ¹¹¹In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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