Document Detail

Effects of lysine-containing mercaptoacetyl-based chelators on the biodistribution of 99mTc-labeled anti-HER2 Affibody molecules.
MedLine Citation:
PMID:  19035668     Owner:  NLM     Status:  MEDLINE    
The effects of polar (mercaptoacetyl-triseryl) and negatively charged (mercaptoacetyl-triglumatyl) chelators on the biodistribution of 99mTc-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 99mTc-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 99mTc 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 chelating sequence. The radioactivity in the gastrointestinal tract was reduced 3-fold for the 99mTc-maSKS-Z(HER2:342) and 99mTc-maKKK-Z(HER2: 342) in comparison with the 99mTc-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 99mTc-maSKS-Z(HER2:342) were further investigated in SKOV-3 xenografts. The tumor uptake of 99mTc-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.
Thuy A Tran; Torun Ekblad; Anna Orlova; Mattias Sandström; Joachim Feldwisch; Anders Wennborg; Lars Abrahmsén; Vladimir Tolmachev; Amelie Eriksson Karlström
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Bioconjugate chemistry     Volume:  19     ISSN:  1520-4812     ISO Abbreviation:  Bioconjug. Chem.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-26     Completed Date:  2009-01-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9010319     Medline TA:  Bioconjug Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2568-76     Citation Subset:  IM    
Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
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MeSH Terms
Antibodies / chemistry,  immunology,  metabolism*
Antibody Specificity
Cell Line, Tumor
Chelating Agents / chemical synthesis,  chemistry,  pharmacology*
Organotechnetium Compounds / chemistry,  metabolism*
Peptides / chemical synthesis,  chemistry,  pharmacology
Radionuclide Imaging
Receptor, erbB-2 / immunology*
Recombinant Fusion Proteins / chemistry,  immunology,  metabolism,  pharmacokinetics*
Staining and Labeling
Thioglycolates / chemistry*
Tissue Distribution / drug effects
Transplantation, Heterologous
Reg. No./Substance:
0/Antibodies; 0/Chelating Agents; 0/Organotechnetium Compounds; 0/Peptides; 0/Recombinant Fusion Proteins; 0/Thioglycolates; 56-87-1/Lysine; 68-11-1/2-mercaptoacetate; EC, erbB-2

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