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186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours

Orlova, Anna ; Tran, Thuy A. ; Ekblad, Torun ; Karlström, Amelie Eriksson ; Tolmachev, Vladimir

European journal of nuclear medicine and molecular imaging, 2010-02, Vol.37 (2), p.260-269 [Periódico revisado por pares]

Berlin/Heidelberg: Springer-Verlag

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  • Título:
    186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours
  • Autor: Orlova, Anna ; Tran, Thuy A. ; Ekblad, Torun ; Karlström, Amelie Eriksson ; Tolmachev, Vladimir
  • Assuntos: Breast cancer ; Cancer ; Cardiology ; Gene expression ; Imaging ; Medicine ; Medicine & Public Health ; Molecular biology ; Nuclear Medicine ; Oncology ; Original Article ; Orthopedics ; Proteins ; Radiology
  • É parte de: European journal of nuclear medicine and molecular imaging, 2010-02, Vol.37 (2), p.260-269
  • Descrição: Purpose Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z HER2:342 has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for 99m Tc-labelling, we have found that synthetic Z HER2:342 conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. Methods maGGG-Z HER2:342 and maGSG-Z HER2:342 were labelled with 186 Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by 186 Re-maGSG-Z HER2:342 were studied. Results Gluconate-mediated labelling of maGGG-Z HER2:342 and maGSG-Z HER2:342 with 186 Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both 186 Re-maGGG-Z HER2:342 and 186 Re-maGSG-Z HER2:342 demonstrated lower renal uptake than their 99m Tc-labelled counterparts. 186 Re-maGSG-Z HER2:342 provided the lowest uptake in healthy tissues. Biodistribution of 186 Re-maGSG-Z HER2:342 in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84±0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Conclusion Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.
  • Editor: Berlin/Heidelberg: Springer-Verlag
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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