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.
|Журнал||European Journal of Nuclear Medicine and Molecular Imaging|
|Состояние||Опубликовано - мар 2012|
|Опубликовано для внешнего пользования||Да|
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging