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Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
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. , p. 51
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 22
Keywords [en]
Inorganic chemistry, 9-Aminoacridine, Daunorubicin, Doxorubicin, Carborane, Radiobromination, Radioiodination, Affibody, Monoclonal antibody
Keywords [sv]
Oorganisk kemi
National Category
Inorganic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-4817ISBN: 91-554-6165-4 (print)OAI: oai:DiVA.org:uu-4817DiVA, id: diva2:165873
Public defence
2005-04-25, Room B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2005-03-04 Created: 2005-03-04 Last updated: 2009-11-23Bibliographically approved
List of papers
1. Synthesis and Radioiodination of Some 9-Aminoacridine Derivatives
Open this publication in new window or tab >>Synthesis and Radioiodination of Some 9-Aminoacridine Derivatives
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2004 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 17, p. 3719-3725Article in journal (Refereed) Published
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-69939 (URN)10.1002/ejoc.200400296 (DOI)
Available from: 2006-05-17 Created: 2006-05-17 Last updated: 2017-11-21Bibliographically approved
2. Synthesis and radioiodination of some 9-aminoacridine derivatives for potential use in radionuclide therapy
Open this publication in new window or tab >>Synthesis and radioiodination of some 9-aminoacridine derivatives for potential use in radionuclide therapy
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2005 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 48, no 12, p. 855-871Article in journal (Refereed) Published
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-83610 (URN)10.1002/jlcr.960 (DOI)
Available from: 2006-11-07 Created: 2006-11-07 Last updated: 2017-12-14Bibliographically approved
3. Synthesis and radioiodination of some daunorubicin and doxorubicin derivatives
Open this publication in new window or tab >>Synthesis and radioiodination of some daunorubicin and doxorubicin derivatives
2005 (English)In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 340, no 1, p. 15-24Article in journal (Refereed) Published
Abstract [en]

Daunorubicin and doxorubicin are efficient agents for cancer treatment. Their clinical efficacy is, however, hampered by their indiscriminant toxicity. This problem may be circumvented by encapsulating the drugs in liposomes and selectively targeting the tumor cells using tumor targeting agents. Furthermore, the antitumor effect could be enhanced by attaching the Auger electron emitter, 125I, to daunorubicin an ddoxorubicin derivatives. In this context a number of ester, amide, and amine derivatives of daunorubicin an ddoxorubicin were synthesized. Benzoic acid ester derivatives of daunorubicin were synthesized by nucleophilic esterification of the 14-bromodaunorubicin with the potassium salt of the corresponding benzoic acid, resulting in good yields. Nicotinic acids and benzoic acids, activated with a succinimidyl group, were coupled to the amino group of daunorubicien to give the corresponding amide derivatives. Amine derivatives were obtained by the reductive amination of aromatic aldehydes with daunorubicin hydrochloride. The stannylated ester and amide derivatives were uses as precursors for radioiodination. Radiolabeling with 125I was performed using chloroamine-T as an oxidant. The optimized labeling resulted in high radiolabeling yields (85-95%) of the radioiodinated daunorubicin and doxorubicin derivatives. Radioiodination of the amines was conducted at the ortho position of the activated phenyl rings providing moderate radiochemical yields (55-75%).

Keywords
Daunorubicin, Doxorubicin, Radioiodination, 125I, Chloramine-T
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-70001 (URN)doi:10.1016/j.carres.2004.10.014 (DOI)15620662 (PubMedID)
Available from: 2006-06-29 Created: 2006-06-29 Last updated: 2017-11-21Bibliographically approved
4. Radiobromination of closo-carboranes using palladium-catalyzed halogen exchange
Open this publication in new window or tab >>Radiobromination of closo-carboranes using palladium-catalyzed halogen exchange
2005 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 48, no 3, p. 195-202Article in journal (Refereed) Published
Keywords
halogen exchange, carboranes, [76Br]bromide, labelling, palladium, catalyst
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-69999 (URN)10.1002/jlcr.914 (DOI)
Available from: 2005-04-13 Created: 2005-04-13 Last updated: 2017-11-21Bibliographically approved
5. Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET
Open this publication in new window or tab >>Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET
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2005 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 32, no 6, p. 613-22Article in journal (Refereed) Published
Abstract [en]

Combining the specificity of radioimmunoscintigraphy and the high sensitivity of PET in an in vivo detection technique could improve the quality of nuclear diagnostics. Positron-emitting nuclide (76)Br (T(1/2)=16.2 h) might be a possible candidate for labeling monoclonal antibodies (mAbs) and their fragments, provided that the appropriate labeling chemistry has been established. For internalizing antibodies, such as the humanized anti-HER2 monoclonal antibody, trastuzumab, radiobromine label should be residualizing, i.e., ensuring that radiocatabolites are trapped intracellularly after the proteolytic degradation of antibody. This study evaluated the chemistry of indirect radiobromination of trastuzumab using N-succinimidyl 5-(tributylstannyl)-3-pyridinecarboxylate. Literature data indicated that the use of this method provided residualizing properties for iodine and astatine labels on some antibodies. An optimized "one-pot" procedure produced an overall labeling efficiency of 45.5+/-1.2% over 15 min. The bromine label was stable under physiological and denaturing conditions. The labeled trastuzumab retained its capacity to bind specifically to HER2-expressing SKOV-3 ovarian carcinoma cells in vitro (immunoreactivity more than 75%). However, in vitro cell test did not demonstrate that the radiobromination of trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate improves cellular retention of radioactivity in comparison with the use of N-succinimidyl 4-bromobenzoate.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-104548 (URN)10.1016/j.nucmedbio.2005.04.010 (DOI)16026708 (PubMedID)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
6. Evaluation of ((4-Hydroxyphenyl)ethyl)maleimide for Site-Specific Radiobromination of Anti-HER2 Affibody
Open this publication in new window or tab >>Evaluation of ((4-Hydroxyphenyl)ethyl)maleimide for Site-Specific Radiobromination of Anti-HER2 Affibody
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2005 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 16, no 6, p. 1547-1555Article 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.

Keywords
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
Identifiers
urn:nbn:se:uu:diva-74804 (URN)10.1021/bc050056o (DOI)16287254 (PubMedID)
Available from: 2006-06-29 Created: 2006-06-29 Last updated: 2017-12-14Bibliographically approved

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