99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule

被引:77
作者
Engfeldt, Torun
Tran, Thuy
Orlova, Anna
Widstroem, Charles
Feldwisch, Joachim
Abrahmsen, Lars
Wennborg, Anders
Karlstroem, Amelie Eriksson
Tolmachev, Vladimir [1 ]
机构
[1] Uppsala Univ, Rudbeck Lab, Unit Biomed Radiat Sci, Uppsala, Sweden
[2] Royal Inst Technol, Sch Biotechnol, Stockholm, Sweden
[3] Affibody AB, Bromma, Sweden
[4] Univ Uppsala Hosp, Dept Oncol, Sect Hosp Phys, S-75185 Uppsala, Sweden
关键词
affibody molecule; HER2; peptide synthesis; technetium-99m; tumour targeting;
D O I
10.1007/s00259-007-0474-6
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
Purpose Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z(HER2:342) binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z(HER2:342) with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with Tc-99m and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z(HER2:342) can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. Methods The Affibody molecule Z(HER2:342), carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D-seryl-glycyl [maG(D-S) G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with Tc-99m. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of Tc-99m-maSSS-Z(HER2): (342) was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z(HER2:342). Results A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of Tc-99m-maSSS-Z(HER2:342) was 11.5 +/- 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z(HER2:342) were better than those of radioiodinated Z(HER2:342). Conclusion The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z(HER2:342) compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.
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页码:1843 / 1853
页数:11
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