| Development and preclinical characterisation of 99mTc-labelled Affibody molecules with reduced renal uptake. | |
| | |
MedLine Citation:
|
PMID: 18594815 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
PURPOSE: Affibody molecules are low molecular weight proteins (7 kDa), which can be selected to bind to tumour-associated target proteins with subnanomolar affinity. Because of rapid tumour localisation and clearance from nonspecific compartments, Affibody molecules are promising tracers for molecular imaging. Earlier, (99m)Tc-labelled Affibody molecules demonstrated specific targeting of tumour xenografts. However, the biodistribution was suboptimal either because of hepatobiliary excretion or high renal uptake of the radioactivity. The goal of this study was to optimise the biodistribution of Affibody molecules by chelator engineering. MATERIALS AND METHODS: Anti-HER2 Z(HER2:342) Affibody molecules, carrying the mercaptoacetyl-glutamyl-seryl-glutamyl (maESE), mercaptoacetyl-glutamyl-glutamyl-seryl (maEES) and mercaptoacetyl-seryl-glutamyl-glutamyl (maSEE) chelators, were prepared by peptide synthesis and labelled with (99m)Tc. The tumour-targeting capacity of these conjugates was compared with each other and with the best previously available conjugate, (99m)Tc-maEEE-Z(HER2:342,) in nude mice bearing SKOV-3 xenografts. The tumour-targeting capacity of the most promising conjugate, (99m)Tc-maESE-Z(HER2:342,) was compared with radioiodinated Z(HER2:342). RESULTS: All novel conjugates demonstrated successful tumour targeting and a low degree of hepatobiliary excretion. The renal uptakes of serine-containing conjugates, 33 +/- 5, 68 +/- 21 and 71 +/- 10%IA/g, for(99m)Tc-maESE-Z(HER2:342), (99m)Tc-maEES-Z(HER2:342) and (99m)Tc-maSEE-Z(HER2:342), respectively, were significantly reduced in comparison with (99m)Tc-maEEE-Z(HER2:342) (102 +/- 13%IA/g). For (99m)Tc-maESE-Z(HER2:342), a tumour uptake of 9.6 +/- 1.8%IA/g and a tumour-to-blood ratio of 58 +/- 6 were reached at 4 h p.i. CONCLUSIONS: A combination of serine and glutamic acid residues in the chelator sequence confers increased renal excretion and relatively low renal uptake of (99m)Tc-labelled Affibody molecules. In combination with preserved targeting capacity, this improved imaging of targets in abdominal area. |
| | |
Authors:
|
Torun Ekblad; Thuy Tran; Anna Orlova; Charles Widström; Joachim Feldwisch; Lars Abrahmsén; Anders Wennborg; Amelie Eriksson Karlström; Vladimir Tolmachev |
Related Documents
:
|
1031415 - Experimental model for studying the invasive characteristics of malignant tumours trans... 2417405 - The pleomorphic adenoma of salivary glands transplanted on athmymic mice. a lightmicros... 14603255 - Wt1 is a modifier of the pax2 mutant phenotype: cooperation and interaction between wt1... 18159975 - Effect of homeopathic medicines on transplanted tumors in mice. 8730425 - Tenascin is an ubiquitous extracellular matrix protein of human renal interstitium in n... 2502055 - Lung rejection and bronchial hyperresponsiveness to methacholine and ultrasonically neb... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-07-02 |
Journal Detail:
|
Title: European journal of nuclear medicine and molecular imaging Volume: 35 ISSN: 1619-7089 ISO Abbreviation: Eur. J. Nucl. Med. Mol. Imaging Publication Date: 2008 Dec |
Date Detail:
|
Created Date: 2008-12-16 Completed Date: 2009-03-09 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 101140988 Medline TA: Eur J Nucl Med Mol Imaging Country: Germany |
Other Details:
|
Languages: eng Pagination: 2245-55 Citation Subset: IM |
Affiliation:
|
School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Cell Line, Tumor Chelating Agents / chemical synthesis, chemistry, metabolism Drug Evaluation, Preclinical / methods* Glutamic Acid Humans Kidney / metabolism* Mice Organotechnetium Compounds / metabolism* Peptides / chemical synthesis, chemistry, metabolism Protein Stability Recombinant Fusion Proteins / metabolism*, pharmacokinetics* Serine Staining and Labeling Tissue Distribution Transplantation, Heterologous |
| Chemical | |
Reg. No./Substance:
|
0/Chelating Agents; 0/Organotechnetium Compounds; 0/Peptides; 0/Recombinant Fusion Proteins; 56-45-1/Serine; 56-86-0/Glutamic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Various image findings of skeletal muscle metastases with clinical correlation.
Next Document: Topotecan enhances immune clearance of gliomas.