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Evaluation of ((4-Hydroxyphenyl)ethyl)maleimide for Site-Specific Radiobromination of Anti-HER2 Affibody
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.ORCID iD: 0000-0001-6120-2683
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2005 (English)In: Bioconjugate chemistry, ISSN 1043-1802, Vol. 16, no 6, 1547-1555 p.Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are a new class of small phage-display selected proteins using a scaffold domain of the bacterial receptor protein A. They can be selected for specific binding to a large variety of protein targets. An affibody molecule binidng with high affinity to a tumor antigen HER2 was recently developed for radionuclide diagnostics and therapy in vivo. The use of hte positron-emitting nuclide 76Br(T½ = 16.2 h) could imporve the sensitivity of detection of HER2-expressing tumors. A site-specific radiobromination o fa cysteine-containing variant of the anti-HER2 affibody, (ZHER2:4)2-Cys, using ((4-hydroxpyphenyl)ethyl)maleimide (HPEM), was evaluated in this study. It was found that HPEM can be radiobrominated with an efficiency of 83+0.4% and thereafter coupled to freshly reduced conjugate to exceed 97%. The label was stable against challenge with large excess of nonlabeled bromide and in a high molar strengt solution. In vitro cell tests demonstraded that radiobrominated affibody binds specifically to the HER2-expressing cel-line, SK-OV-3. Biodistribution studies in nude mice bearing SK-OV-3 xenografts have shown tumor accumulation of 4.8 ? 2.2% IA/g and good tumor-to-normal tissue ratios.

Place, publisher, year, edition, pages
2005. Vol. 16, no 6, 1547-1555 p.
Keyword [en]
Animals, Antigens; Neoplasm/analysis/metabolism, Binding Sites, Bromine Radioisotopes/*chemistry, Cell Line; Tumor, Humans, Maleimides/chemistry, Mice, Mice; Nude, Neoplasms; Experimental/pathology, Peptide Library, Peptides/chemistry/*pharmacokinetics, Protein Interaction Mapping, Radiopharmaceuticals/*chemical synthesis/*pharmacokinetics, Receptor; erbB-2/analysis/*metabolism, Research Support; Non-U.S. Gov't, Staphylococcal Protein A/chemistry, Tissue Distribution, Transplantation; Heterologous
National Category
Organic Chemistry
URN: urn:nbn:se:uu:diva-74804DOI: 10.1021/bc050056oPubMedID: 16287254OAI: oai:DiVA.org:uu-74804DiVA: diva2:102714
Available from: 2006-06-29 Created: 2006-06-29 Last updated: 2015-03-24Bibliographically approved
In thesis
1. Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
Open this publication in new window or tab >>Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis and radiohalogenation of compounds of potential use for tumor targeting.

The first section describes the synthesis and radioiodination of DNA intercalating compounds. The compounds are derivatives of 9-aminoacridine, and the anthracyclins daunorubicin and doxorubicin. The precursor compounds were labeled with 125I (T1/2 = 60 days), which is an Auger emitting nuclide. 125I decaying in the close vicinity of DNA is known to have a much higher cell killing effect than 125I decaying in the cytoplasm and some of the labeled compounds prepared in this thesis are currently being tested for use in targeted radionuclide therapy for cancer.

The second section describes the radiobromination of closo-carboranes by subjecting the corresponding iodinated compounds to palladium-catalyzed halogen exchange using [76Br]bromide. The 76Br isotope (T1/2 = 16.2 h) is a positron emitting nuclide that is suitable for PET studies. Via the halogen exchange reaction good to excellent radiochemical yields of radiobrominated closo-carboranes were obtained. The results of the present study may prove to be applicable to pharmacokinetic studies of carboranes and their derivatives.

The third and final section describes the indirect radiobromination of the trastuzumab anti-HER2 monoclonal antibody and of the anti-HER2 Affibody by means of an “one-pot” procedure using N-succinimidyl-5-(tributylstannyl)-3-pyridinecarboxylate (SPC) and ((4-hydroxyphenyl)ethyl))maleimide (HPEM), respectively. It was found that SPC and HPEM can be efficiently radiobrominated and thereafter coupled to the antibody and Affibody, respectively. The labeled proteins retained their capacity to bind specifically to HER2 expressing SKOV-3 cells in vitro. Application of this method to 76Br might enable the use of PET in the detection of HER2 expression in breast, ovarian, and urinary bladder carcinomas.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 22
Inorganic chemistry, 9-Aminoacridine, Daunorubicin, Doxorubicin, Carborane, Radiobromination, Radioiodination, Affibody, Monoclonal antibody, Oorganisk kemi
National Category
Inorganic Chemistry
urn:nbn:se:uu:diva-4817 (URN)91-554-6165-4 (ISBN)
Public defence
2005-04-25, Room B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Available from: 2005-03-04 Created: 2005-03-04 Last updated: 2009-11-23Bibliographically approved

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Mume, EskenderOrlova, AnnaSjöberg, StefanTolmachev, Vladimir
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