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

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

Результат исследований: Материалы для журналаСтатьярецензирование

33 Цитирования (Scopus)

Аннотация

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 HER2:342Affibody 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:S1provided 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.

Язык оригиналаАнглийский
Страницы (с-по)481-492
Число страниц12
ЖурналEuropean Journal of Nuclear Medicine and Molecular Imaging
Том39
Номер выпуска3
DOI
СостояниеОпубликовано - мар 2012
Опубликовано для внешнего пользованияДа

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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