Effects of Lysine-Containing Mercaptoacetyl-Based Chelators on the Biodistribution of Tc-99m-Labeled Anti-HER2 Affibody Molecules

• The effects of polar (mercaptoacetyl-triseryl) and negatively charged (mercaptoacetyl-triglumatyl) chelators on the biodistribution of Tc-99m-labeled anti-HER2 Affibody molecules were previously investigated. With glycine, serine, and glutamate, we demonstrated that substitution with a single amino acid in the chelator can significantly influence the biodistribution properties and the excretion pathways. Here, we have taken this investigation further, by analyzing the effects of introduction of a positive amino acid residue on the in vivo properties of the Tc-99m-labeled Affibody molecule. The Affibody molecules with mercaptoacetyl-seryl-lysyl-seryl (maSKS) and mercaptoacetyl-trilysyl (maKKK) extensions were produced by peptide synthesis and labeled with Tc-99m in alkaline conditions. A comparative biodistribution was performed in normal mice to evaluate the excretion pathway. A shift toward renal excretion was obtained when serine was substituted with lysine in the chelatin sequence. The radioactivity in the gastrointestinal tract was reduced 3-fold for the Tc-99m-maSKS-Z(HER2:342) and Tc-99m-maKKK-Z(HER2:342) in comparison with the Tc-99m-maSSS-Z(HER2:342) conjugate 4 h post injection (p.i.). The radioactivity in the liver was elevated when a triple substitution of positively charged lysine was used. The tumor targeting properties of Tc-99m-maSKS-Z(HER2:342) were further investigated in SKOV-3 xenografts. The tumor uptake of Tc-99m-maSKS-Z(HER2:342) was 17 +/- 7% IA/g 4 h p.i. Tumor xenografts were well-visualized by gamma scintigraphy. In conclusion, the substitution with one single lysine in the chelator results in better tumor imaging properties of the Affibody molecule Z(HER2:342) and is favorable for imaging of tumors and metastases in the abdominal area. Multiple lysine residues in the chelator are, however, undesirable due to elevated uptake both in the liver and kidneys.

Nyckelord

of-clinical-oncology

malignant-tumors

her2 expression

breast-cancer

protein

therapy

recommendations

conjugate

chemistry

tc-99m

MEDICINE

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