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Strand, Joanna
Publications (10 of 20) Show all publications
Strand, J. (2015). Affibody Molecules for PET Imaging. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Affibody Molecules for PET Imaging
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Optimization of Affibody molecules would allow for high contrast imaging of cancer associated surface receptors using molecular imaging. The primary aim of the thesis was to develop Affibody-based PET imaging agents to provide the highest possible sensitivity of RTK detection in vivo. The thesis evaluates the effect of radiolabelling chemistry on biodistribution and targeting properties of Affibody molecules directed against HER2 and PDGFRβ. The thesis is based on five published papers (I-V).

Paper I. The targeting properties of maleimido derivatives of DOTA and NODAGA for site-specific labelling of a recombinant HER2-binding Affibody molecule radiolabelled with 68Ga were compared in vivo. Favourable in vivo properties were seen for the Affibody molecule with the combination of 68Ga with NODAGA.

Paper II. The aim was to compare the biodistribution of 68Ga- and 111In-labelled HER2-targeting Affibody molecules containing DOTA, NOTA and NODAGA at the N-terminus. This paper also demonstrated favourable in vivo properties for Affibody molecules in combination with 68Ga and NODAGA placed on the N-terminus.

Paper III.  The influence of chelator positioning on the synthetic anti-HER2 affibody molecule labelled with 68Ga was investigated. The chelator DOTA was conjugated either at the N-terminus, the middle of helix-3 or at the C-terminus of the Affibody molecules. The N-terminus placement provided the highest tumour uptake and tumour-to-organ ratios.

Paper IV. The aim of this study was to evaluate if the 68Ga labelled PDGFRβ-targeting Affibody would provide an imaging agent suitable for PDGFRβ visualization using PET. The 68Ga labelled conjugate provided high-contrast imaging of PDGFRβ-expressing tumours in vivo using microPET as early as 2h after injection.

Paper V. This paper investigated if the replacement of IHPEM with IPEM as a linker molecule for radioiodination of Affibody molecules would reduce renal retention of radioactivity. Results showed that the use of the more lipophilic linker IPEM reduced the renal radioactivity retention for radioiodinated Affibody molecules.

In conclusion, this thesis clearly demonstrates that the labelling strategy is of great importance with a substantial influence on the targeting properties of Affibody molecules and should be taken under serious considerations when developing new imaging agents.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 70
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1125
Keywords
Affibody molecules, Molecular imaging, PET, Radiolabelling, HER2, PDGFRβ
National Category
Medical and Health Sciences
Research subject
Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-259410 (URN)978-91-554-9299-1 (ISBN)
Public defence
2015-10-03, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, 751 85, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-03 Created: 2015-08-03 Last updated: 2015-10-01
Strand, J., Nordeman, P., Honarvar, H., Altai, M., Orlova, A., Larhed, M. & Tolmachev, V. (2015). Site-Specific Radioiodination of HER2-Targeting Affibody Molecules using 4-Iodophenethylmaleimide Decreases Renal Uptake of Radioactivity. ChemistryOpen, 4(2), 174-182
Open this publication in new window or tab >>Site-Specific Radioiodination of HER2-Targeting Affibody Molecules using 4-Iodophenethylmaleimide Decreases Renal Uptake of Radioactivity
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2015 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 4, no 2, p. 174-182Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are small scaffold-based affinity proteins with promising properties as probes for radionuclide-based molecular imaging. However, a high reabsorption of radiolabeled Affibody molecules in kidneys is an issue. We have shown that the use of I-125-3-iodo-((4-hydroxyphenyl)ethyl)maleimide (IHPEM) for site-specific labeling of cysteine-containing Affibody molecules provides high tumor uptake but low radioactivity retention in kidneys. We hypothesized that the use of 4-iodophenethylmaleimide (IPEM) would further reduce renal retention of radioactivity because of higher lipophilicity of radiometabolites. An anti-human epidermal growth factor receptor type2 (HER2) Affibody molecule (Z(HER2:2395)) was labeled using I-125-IPEM with an overall yield of 45 +/- 3%. I-125-IPEM-Z(HER2:2395) bound specifically to HER2-expressing human ovarian carcinoma cells (SKOV-3 cell line). In NMRI mice, the renal uptake of I-125-IPEM-Z(HER2:2395) (24 +/- 2 and 5.7 +/- 0.3%IAg(-1)at 1 and 4 h after injection, respectively) was significantly lower than uptake of I-125-IHPEM-Z(HER2:2395) (50 +/- 8 and 12 +/- 2%IAg(-1)at 1 and 4 h after injection, respectively). In conclusion, the use of a more lipophilic linker for the radioiodination of Affibody molecules reduces renal radioactivity.

Keywords
affibody molecules, drug design, iodophenethylmaleimide, radiolabeling, radiopharmaceuticals
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-253262 (URN)10.1002/open.201402097 (DOI)000353653800014 ()25969816 (PubMedID)
Available from: 2015-05-26 Created: 2015-05-25 Last updated: 2017-12-04Bibliographically approved
Altai, M., Wållberg, H., Honarvar, H., Strand, J., Orlova, A., Varasteh, Z., . . . Tolmachev, V. (2014). 188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment. Journal of Nuclear Medicine, 55(11), 1842-1848
Open this publication in new window or tab >>188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment
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2014 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 11, p. 1842-1848Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of 99mTc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide–based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate 188Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)–expressing tumors.

Methods:

ZHER2:V2 was labeled with 188Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.

Results:

Binding of 188Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that 188Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.

Conclusion:

188Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-211593 (URN)10.2967/jnumed.114.140194 (DOI)000344209200015 ()25278516 (PubMedID)
Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
Strand, J., Varasteh, Z., Eriksson, O., Abrahmsen, L., Orlova, A. & Tolmachev, V. (2014). Gallium-68-labeled affibody molecule for PET imaging of PDGFR beta expression in vivo. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN. European Journal of Nuclear Medicine and Molecular Imaging, 41(S2), S262-S262, Article ID OP469.
Open this publication in new window or tab >>Gallium-68-labeled affibody molecule for PET imaging of PDGFR beta expression in vivo
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2014 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S262-S262, article id OP469Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-247706 (URN)000348841900331 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN
Available from: 2015-03-25 Created: 2015-03-23 Last updated: 2017-12-04Bibliographically approved
Strand, J., Varasteh, Z., Eriksson, O., Abrahmsen, L., Orlova, A. & Tolmachev, V. (2014). Gallium-68-Labeled Affibody Molecule for PET Imaging of PDGFRβ Expression in Vivo. Molecular Pharmaceutics, 11(11), 3957-3964
Open this publication in new window or tab >>Gallium-68-Labeled Affibody Molecule for PET Imaging of PDGFRβ Expression in Vivo
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2014 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 11, p. 3957-3964Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor involved, for example, in angiogenesis. Overexpression and excessive signaling of PDGFRβ has been observed in multiple malignant tumors and fibrotic diseases, making this receptor a pharmaceutical target for monoclonal antibodies and tyrosine kinase inhibitors. Successful targeted therapy requires identification of responding patients. Radionuclide molecular imaging would enable determination of the PDGFRβ status in all lesions using a single noninvasive repeatable procedure. Recently, we have demonstrated that the affibody molecule Z09591 labeled with 111In can specifically target PDGFRβ-expressing tumors in vivo. The use of positron emission tomography (PET) as an imaging technique would provide superior resolution, sensitivity, and quantitation accuracy. In this study, a DOTA-conjugated Z09591 was labeled with the generator-produced positron emitting radionuclide 68Ga (T1/2 = 67.6 min, Eβ + max = 1899 keV, 89% β+). 68Ga-DOTA-Z09591 retained the capacity to specifically bind to PDGFRβ-expressing U-87 MG glioma cells. The half-maximum inhibition concentration (IC50) of 68Ga-DOTA-Z09591 (6.6 ± 1.4 nM) was somewhat higher than that of 111In-DOTA-Z09591 (1.4 ± 1.2 nM). 68Ga-DOTA-Z09591 demonstrated specific (saturable) targeting of U-87 MG xenografts in immunodeficient mice. The tumor uptake at 2 h after injection was 3.7 ± 1.7% IA/g, which provided a tumor-to-blood ratio of 8.0 ± 3.1. The only organ with higher accumulation of radioactivity was the kidney. MicroPET imaging provided high-contrast imaging of U-87 MG xenografts. In conclusion, the 68Ga-labeled affibody molecule Z09591 is a promising candidate for further development as a probe for imaging PDGFRβ expression in vivo using PET.

National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-235390 (URN)10.1021/mp500284t (DOI)000344307700020 ()24972112 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2014-11-01 Created: 2014-11-01 Last updated: 2017-12-05Bibliographically approved
Orlova, A., Malm, M., Rosestedt, M., Varasteh, Z., Andersson, K., Selvaraju, R. K., . . . Löfblom, J. (2014). Imaging of HER3-expressing xenografts in mice using a (99m)Tc(CO) 3-HEHEHE-Z HER3 08699 affibody molecule. European Journal of Nuclear Medicine and Molecular Imaging, 41(7), 1450-1459
Open this publication in new window or tab >>Imaging of HER3-expressing xenografts in mice using a (99m)Tc(CO) 3-HEHEHE-Z HER3 08699 affibody molecule
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2014 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no 7, p. 1450-1459Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Human epidermal growth factor receptor type 3 (HER3) is a transmembrane receptor tyrosine kinase belonging to the HER (ErbB) receptor family. Membranous expression of HER3 is associated with trastuzumab resistance in breast cancer and the transition to androgen independence in prostate cancer. Imaging of HER3 expression in malignant tumors may provide important diagnostic information that can influence patient management. Affibody molecules with low picomolar affinity to HER3 were recently selected. The aim of this study was to investigate the feasibility of HER3 imaging using radiolabeled Affibody molecules.

METHODS: A HER3-binding Affibody molecule, Z08699, with a HEHEHE-tag on N-terminus was labeled with (99m)Tc(CO)3 using an IsoLink kit. In vitro and in vivo binding specificity and the cellular processing of the labeled binder were evaluated. Biodistribution of (99m)Tc(CO)3-HEHEHE-Z08699 was studied over time in mice bearing HER3-expressing xenografts.

RESULTS: HEHEHE-Z08699 was labeled with (99m)Tc(CO)3 with an isolated yield of >80 % and a purity of >99 %. Binding of (99m)Tc(CO)3-HEHEHE-Z08699 was specific to BT474 and MCF7 (breast cancer), and LS174T (colon cancer) cells. Cellular processing showed rapid binding and relatively quick internalization of the receptor/Affibody molecule complex (70 % of cell-associated radioactivity was internalized after 24 h). The tumor targeting was receptor mediated and the excretion was predominantly renal. Receptor-mediated uptake was also found in the liver, lung, stomach, intestine, and salivary glands. At 4 h pi, tumor-to-blood ratios were 7 ± 3 for BT474, and 6 ± 2 for LS174T xenografts. LS174T tumors were visualized by microSPECT 4 h pi.

CONCLUSIONS: The results of this study suggest the feasibility of HER3-imaging in malignant tumors using Affibody molecules.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-220474 (URN)10.1007/s00259-014-2733-7 (DOI)000337286200021 ()24622956 (PubMedID)
Available from: 2014-03-15 Created: 2014-03-15 Last updated: 2018-01-11Bibliographically approved
Rosik, D., Thibblin, A., Antoni, G., Honarvar, H., Strand, J., Selvaraju, R. K., . . . Tolmachev, V. (2014). Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with (18)F-4-Fluorobenzaldehyde. Bioconjugate chemistry, 25(1), 82-92
Open this publication in new window or tab >>Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with (18)F-4-Fluorobenzaldehyde
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2014 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 25, no 1, p. 82-92Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are a class of affinity agents for molecular imaging based on a non-immunoglobulin protein scaffold. Previous studies have demonstrated high contrast for in vivo imaging of cancer-associated molecular abnormalities using Affibody molecules. Using the radionuclide (18)F for labeling and PET as the imaging modality, the sensitivity of molecular imaging using Affibody molecules can be further increased. The use of oxime formation between an aminooxy-functionalized peptide and (18)F-fluorobenzaldehyde ((18)F-FBA) is a promising way of radiolabeling of targeting peptides. However, previous studies demonstrated that application of this method to Affibody molecules is associated with high liver uptake. We hypothesized that incorporation of a triglutamyl spacer between the aminooxy moiety and the N-terminus of a synthetic Affibody molecule would decrease the hepatic uptake of the (18)F-N-(4-fluorobenzylidine)oxime) ((18)F-FBO)-labeled tracer. To verify this, we have produced two variants of the HER2-targeting ZHER2:342 Affibody molecule by peptide synthesis: OA-PEP4313, where aminooxyacetic acid was conjugated directly to the N-terminal alanine, and OA-E3-PEP4313, where a triglutamyl spacer was introduced between the aminooxy moiety and the N-terminus. We have found that the use of the spacer is associated with a minor decrease of affinity, from KD = 49 pM to KD = 180 pM. Radiolabeled (18)F-FBO-E3-PEP4313 demonstrated specific binding to HER2-expressing ovarian carcinoma SKOV-3 cells and slow internalization. Biodistribution studies in mice demonstrated that the use of a triglutamyl linker decreased uptake of radioactivity in liver 2.7-fold at 2 h after injection. Interestingly, radioactivity uptake in kidneys was also reduced (2.4-fold). Experiments in BALB/C nu/nu mice bearing SKOV-3 xenografts demonstrated HER2-specific uptake of (18)F-FBO-E3-PEP4313 in tumors. At 2 h pi, the tumor uptake (20 ± 2% ID/g) exceeded uptake in liver 5-fold and uptake in kidneys 3.6-fold. The tumor-to-blood ratio was 21 ± 3. The microPET/CT imaging experiment confirmed the biodistribution data. In conclusion, the use of a triglutamyl spacer is a convenient way to improve the biodistribution profile of Affibody molecules labeled at the N-terminus using (18)F-FBA. It provides a tracer capable of producing high-contrast images of HER2-expressing tumors.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-218569 (URN)10.1021/bc400343r (DOI)000330018400011 ()24344772 (PubMedID)
Available from: 2014-02-12 Created: 2014-02-12 Last updated: 2018-01-11Bibliographically approved
Honarvar, H., Strand, J., Perols, A., Orlova, A., Selvaraju, R. K., Eriksson Karlström, A. & Tolmachev, V. (2014). Position for Site-Specific Attachment of a DOTA Chelator to Synthetic Affibody Molecules Has a Different Influence on the Targeting Properties of 68Ga- Compared to 111In-Labeled Conjugates.. Molecular Imaging, 13, 1-12
Open this publication in new window or tab >>Position for Site-Specific Attachment of a DOTA Chelator to Synthetic Affibody Molecules Has a Different Influence on the Targeting Properties of 68Ga- Compared to 111In-Labeled Conjugates.
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2014 (English)In: Molecular Imaging, ISSN 1535-3508, E-ISSN 1536-0121, Vol. 13, p. 1-12Article in journal (Refereed) Published
Abstract [en]

AbstractAffibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1, which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes.

National Category
Biochemistry and Molecular Biology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-232934 (URN)10.2310/7290.2014.00034 (DOI)000349631400003 ()25249017 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2014-09-27 Created: 2014-09-27 Last updated: 2017-12-05Bibliographically approved
Altai, M., Honarvar, H., Wållberg, H., Strand, J., Varasteh, Z., Rosestedt, M., . . . Ståhl, S. (2014). Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with 188Re. European Journal of Medicinal Chemistry, 87, 519-528
Open this publication in new window or tab >>Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with 188Re
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2014 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 87, p. 519-528Article in journal (Refereed) Published
Abstract [en]

Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

Keywords
Rhenium-188; Affibody; HER2; Peptide-based chelator; Biodistribution; Radionuclide therapy
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-235383 (URN)10.1016/j.ejmech.2014.09.082 (DOI)000363431300049 ()25282673 (PubMedID)
Available from: 2014-11-01 Created: 2014-11-01 Last updated: 2017-12-05Bibliographically approved
Orlova, A., Hofström, C., Strand, J., Varasteh, Z., Sandström, M., Andersson, K., . . . Gräslund, T. (2013). [99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours. European Journal of Nuclear Medicine and Molecular Imaging, 40(3), 439-449
Open this publication in new window or tab >>[99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours
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2013 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no 3, p. 439-449Article in journal (Refereed) Published
Abstract [en]

Purpose

Radionuclide imaging of insulin-like growth factor type 1 receptor (IGF-1R) expression in tumours might be used for selection of patients who would benefit from IGF-1R-targeted therapy. We have previously shown the feasibility of IGF-1R imaging using the Affibody molecule 111In-DOTA-His6-ZIGF1R:4551. The use of 99mTc instead of 111In should improve sensitivity and resolution of imaging, and reduce the dose burden to patients. We hypothesized that inclusion of a HEHEHE tag instead of a His6 tag in ZIGF1R:4551 would permit its convenient purification using IMAC, enable labelling with [99mTc(CO)3]+, and improve its biodistribution.

Methods

ZIGF1R:4551 was expressed with a HEHEHE tag in the N terminus. The resulting (HE)3-ZIGF1R:4551 construct was labelled with [99mTc(CO)3]+. Targeting of IGF-1R-expressing cells using [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 was evaluated in vitro and in vivo.

Results

(HE)3-ZIGF1R:4551 was stably labelled with 99mTc with preserved specific binding to IGF-1R-expressing DU-145 prostate cancer cells in vitro. In mice, [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 accumulated in IGF-1R-expressing organs (pancreas, stomach, lung and salivary gland). [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 demonstrated 3.6-fold lower accumulation in the liver and spleen than 111In-DOTA-ZIGF1R:4551. In NMRI nu/nu mice with DU-145 prostate cancer xenografts, the tumour uptake was 1.32 ± 0.11 %ID/g and the tumour-to-blood ratio was 4.4 ± 0.3 at 8 h after injection. The xenografts were visualized using a gamma camera 6 h after injection.

Conclusion

99mTc(CO)3]+-(HE)3-ZIGF1R:4551 is a promising candidate for visualization of IGF-1R expression in malignant tumours.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-196212 (URN)10.1007/s00259-012-2284-8 (DOI)000314676900015 ()23179942 (PubMedID)
Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2018-01-11Bibliographically approved
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