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Publications (10 of 202) Show all publications
Summer, D., Garousi, J., Oroujeni, M., Mitran, B., Andersson, K. G., Vorobyeva, A., . . . Decristoforo, C. (2018). Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression. Molecular Pharmaceutics, 15(1), 175-185
Open this publication in new window or tab >>Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 1, p. 175-185Article in journal (Refereed) Published
Abstract [en]

Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow e pharmacokinetics as due to its longer half-life, in comparison to fluorine 18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to head as bifunctional chelators for "Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFOZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 degrees C. Both 89Zr-FSC-ZEGFR:2377 and Zr-89-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 degrees C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89ZrDFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of Zr-89-FSC-ZEGFR:2377 as well as Zr-89-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that Zr-89-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
Keywords
FSC, DFO, zirconium-89, EGFR, affibody, PET
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-341305 (URN)10.1021/acs.molpharmaceut.7b00787 (DOI)000419419800017 ()29160082 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/474, CAN2015/350Swedish Research Council, VR 2015-02509, VR 2015-02353Knut and Alice Wallenberg Foundation
Available from: 2018-02-07 Created: 2018-02-07 Last updated: 2018-02-07Bibliographically approved
Honarvar, H., Calce, E., Doti, N., Langella, E., Orlova, A., Buijs, J., . . . De Luca, S. (2018). Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe. Scientific Reports, 8, Article ID 2998.
Open this publication in new window or tab >>Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2998Article in journal (Refereed) Published
Abstract [en]

HER2 transmembrane receptor is an important target in immunotherapy treatment of breast and gastroesophageal cancer. Molecular imaging of HER2 expression may provide essential prognostic and predictive information concerning disseminated cancer and aid in selection of an optimal therapy. Radiolabeled low molecular weight peptide ligands are particularly attractive as probes for molecular imaging, since they reach and bind to the target and clear from non-target organs and blood stream faster than bulky antibodies. In this study, we evaluated a potential HER2-imaging probe, an A9 nonapeptide, derived from the trastuzumab-Fab portion. Its cellular uptake was investigated by mass spectrometry analysis of the cytoplasmic cellular extracts. Moreover, based on in-silico modeling, DTPA chelator was conjugated to N-terminus of A9. In-111-labeled A9 demonstrated nanomolar affinity to HER2-expressing BT474 cells and favorable biodistribution profile in NMRI mice. This study suggests that the peptide A9 represents a good lead candidate for development of molecular probe, to be used for imaging purposes and for the delivery of cytotoxic agents.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-348106 (URN)10.1038/s41598-018-21283-3 (DOI)000424985800036 ()29445216 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/350Swedish Research Council, 2015-02353
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved
Lindbo, S., Garousi, J., Mitran, B., Buijs, J., Altai, M., Orlova, A., . . . Tolmachev, V. (2018). Radionuclide tumor targeting using ADAPT scaffold proteins: aspects of label positioning and residualizing properties of the label. Journal of Nuclear Medicine, 59(1), 93-99
Open this publication in new window or tab >>Radionuclide tumor targeting using ADAPT scaffold proteins: aspects of label positioning and residualizing properties of the label
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2018 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 1, p. 93-99Article in journal (Refereed) Published
Abstract [en]

Visualization of cancer-associated alterations of molecular phenotype using radionuclide imaging is a noninvasive approach to stratifying patients for targeted therapies. The engineered albumin-binding domain-derived affinity protein (ADAPT) is a promising tracer for radionuclide molecular imaging because of its small size (6.5 kDa), which satisfies the precondition for efficient tumor penetration and rapid clearance. Previous studies demonstrated that the human epidermal growth factor receptor type 2 (HER2)-targeting ADAPT6 labeled with radiometals at the N terminus is able to image HER2 expression in xenografts a few hours after injection. The aim of this study was to evaluate whether the use of a non-residualizing label or placement of the labels at the C terminus would further improve the targeting properties of ADAPT6. Methods: Two constructs, Cys(2)-ADAPT6 and Cys(59)-ADAPT6, having the (HE)(3)DANS sequence at the N terminus were produced and site-specifically labeled using In-111-DOTA or I-125-iodo-((4-hydroxyphenyl) ethyl) maleimide (HPEM). The conjugates were compared in vitro and in vivo. HER2-targeting properties and biodistribution were evaluated in BALB/C nu/nu mice bearing ovarian carcinoma cell (SKOV-3) xenografts. Results: Specific HER2 binding and high affinity were preserved after labeling. Both Cys(2)-ADAPT6 and Cys59-ADAPT6 were internalized slowly by HER2-expressing cancer cells. Depending on the label position, uptake at 4 h after injection varied from 10% to 22% of the injected dose per gram of tumor tissue. Regardless of terminus position, the I-125-HPEM label provided more than 140-fold lower renal uptake than the In-111-DOTA label at 4 after injection. The tumor-to-organ ratios were, in contrast, higher for both of the (111)InDOTA- labeled ADAPT variants in other organs. Tumor-to-blood ratios for In-111-labeled Cys(2)-ADAPT6 and Cys(59)-ADAPT6 did not differ significantly (250-280), but In-111-DOTA-Cys(59)-ADAPT6 provided significantly higher tumor-to-lung, tumor-to-liver, tumor-to-spleen, and tumor-to-muscle ratios. Radioiodinated variants had similar tumor-to-organ ratios, but I-125-HPEM-Cys(59)-ADAPT6 had significantly higher tumor uptake and a higher tumor-to-kidney ratio. Conclusion: Residualizing properties of the label strongly influence the targeting properties of ADAPT6. The position of the radiolabel influences targeting as well, although to a lesser extent. Placement of a label at the C terminus yields the best biodistribution features for both radiometal and radiohalogen labels. Low renal retention of the radioiodine label creates a precondition for radionuclide therapy using I-131-labeled HPEM-Cys(59)-ADAPT6.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-327415 (URN)10.2967/jnumed.117.197202 (DOI)000419116200021 ()28864631 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2018-02-07Bibliographically approved
Tolmachev, V., Yim, C.-B., Rajander, J., Perols, A., Karlstrom, A. E., Haaparanta-Solin, M., . . . Orlova, A. (2017). Comparative Evaluation of Anti-HER2 Affibody Molecules Labeled with Cu-64 Using NOTA and NODAGA. Contrast Media & Molecular Imaging, 1-12
Open this publication in new window or tab >>Comparative Evaluation of Anti-HER2 Affibody Molecules Labeled with Cu-64 Using NOTA and NODAGA
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2017 (English)In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, p. 1-12Article in journal (Refereed) Published
Abstract [en]

Imaging using affi body molecules enables discrimination between breast cancer metastases with high and low expression of HER2, making appropriate therapy selection possible. This study aimed to evaluate if the longer half-life of Cu-64 (T-1/2 = 12.7h) would make Cu-64 a superior nuclide compared to Ga-68 for PET imaging of HER2 expression using affibody molecules. The synthetic ZHER2: S1 affibody molecule was conjugated with the chelators NOTA or NODAGA and labeled with Cu-64. The tumor-targeting properties of Cu-64-NOTA-ZHER2: S1 and Cu-64-NODAGA-ZHER2: S1 were evaluated and compared with the targeting properties of Ga-68-NODAGA-ZHER2: S1 in mice. Both 64 Cu-NOTA-ZHER2: S1 and Cu-64-NODAGA-ZHER2: S1 demonstrated specific targeting of HER2-expressing xenografts. At 2 h after injection of Cu-64-NOTA-ZHER2: S1, Cu-64-NODAGA-ZHER2: S1, and Ga-68-NODAGAZHER2: S1, tumor uptakes did not differ significantly. Renal uptake of Cu-64-labeled conjugateswas dramatically reduced at 6 and 24 h after injection. Notably, radioactivity uptake concomitantly increased in blood, lung, liver, spleen, and intestines, which resulted in decreased tumor-to-organ ratios compared to 2 h postinjection. Organ uptake was lower for Cu-64-NODAGA-ZHER2: S1. The most probable explanation for this biodistribution pattern was the release and redistribution of renal radiometabolites. In conclusion, monoamide derivatives of NOTA and NODAGA may be suboptimal chelators for radiocopper labeling of anti-HER2 affibody molecules and, possibly, other scaffold proteins with high renal uptake.

Place, publisher, year, edition, pages
WILEY-HINDAWI, 2017
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-322000 (URN)10.1155/2017/8565802 (DOI)000399198500001 ()
Funder
Swedish Cancer Society, CAN 2015/350 2014/474Swedish Research Council, 2015-02353 2013-5135 2015-02509
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2017-05-31Bibliographically approved
Garousi, J., Lindbo, S., Mitran, B., Buijs, J., Vorobyeva, A., Orlova, A., . . . Hober, S. (2017). Comparative evaluation of tumor targeting using the anti-HER2 ADAPT scaffold protein labeled at the C-terminus with indium-111 or technetium-99m. Scientific Reports, 7, Article ID 14780.
Open this publication in new window or tab >>Comparative evaluation of tumor targeting using the anti-HER2 ADAPT scaffold protein labeled at the C-terminus with indium-111 or technetium-99m
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 14780Article in journal (Refereed) Published
Abstract [en]

ABD-Derived Affinity Proteins (ADAPTs) is a novel class of engineered scaffold proteins derived from an albumin-binding domain of protein G. The use of ADAPT6 derivatives as targeting moiety have provided excellent preclinical radionuclide imaging of human epidermal growth factor 2 (HER2) tumor xenografts. Previous studies have demonstrated that selection of nuclide and chelator for its conjugation has an appreciable effect on imaging properties of scaffold proteins. In this study we performed a comparative evaluation of the anti-HER2 ADAPT having an aspartate-glutamate-alanine-valine-aspartate-alanine-asparagine-serine (DEAVDANS) N-terminal sequence and labeled at C-terminus with (99)mTc using a cysteine-containing peptide based chelator, glycine-serine-serine-cysteine (GSSC), and a similar variant labeled with In-111 using a maleimido derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. Both (99)mTc-DEAVDANS-ADAPT6-GSSC and In-111-DEAVDANS-ADAPT6-GSSC-DOTA accumulated specifically in HER2-expressing SKOV3 xenografts. The tumor uptake of both variants did not differ significantly and average values were in the range of 19-21% ID/g. However, there was an appreciable variation in uptake of conjugates in normal tissues that resulted in a notable difference in the tumor-to-organ ratios. The In-111-DOTA label provided 2-6 fold higher tumor-to-organ ratios than (99)mTc-GSSC and is therefore the preferable label for ADAPTs.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-341936 (URN)10.1038/s41598-017-15366-w (DOI)000414569900003 ()29116215 (PubMedID)
Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2018-02-16Bibliographically approved
Rosestedt, M., Andersson, K. G., Mitran, B., Rinne, S. S., Tolmachev, V., Löfblom, J., . . . Ståhl, S. (2017). Evaluation of radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression. International Journal of Oncology, 51(6), 1765-1774
Open this publication in new window or tab >>Evaluation of radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression
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2017 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 51, no 6, p. 1765-1774Article in journal (Refereed) Published
Abstract [en]

The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated. Preclinical studies have shown that the contrast when imaging using anti-HER3 affibody molecules can be improved over time. We aim to develop an agent for PET imaging of HER3 expression using the long-lived positron-emitting radionuclide cobalt-55 (55Co) (T1/2=17.5 h). A long-lived cobalt isotope 57Co was used as a surrogate for 55Co in this study. The anti-HER3 affibody molecule HEHEHE-ZHER3-NOTA was labelled with radiocobalt with high yield, purity and stability. Biodistribution of 57Co-HEHEHE-ZHER3-NOTA was measured in mice bearing DU145 (prostate carcinoma) and LS174T (colorectal carcinoma) xenografts at 3 and 24 h post injection (p.i.). Tumour-to-blood ratios significantly increased between 3 and 24 h p.i. (p<0.05). At 24 h p.i., tumour-to-blood ratios were 6 for DU145 and 8 for LS174T xenografts, respectively. HER3‑expressing xenografts were clearly visualized in a preclinical imaging setting already 3 h p.i., and contrast further improved at 24 h p.i. In conclusion, the radiocobalt-labelled anti-HER3 affibody molecule, HEHEHE-ZHER3-NOTA, is a promising tracer for imaging of HER3 expression in tumours.

Keywords
HER3, affibody, PET imaging, Cobalt-55/57, NOTA-chelator
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-343404 (URN)10.3892/ijo.2017.4152 (DOI)000416685600014 ()
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society, CAN2014/474Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Research Council, 2012-05236Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN2016/463VINNOVA, 2016-04060
Available from: 2018-02-27 Created: 2018-02-27 Last updated: 2018-05-29Bibliographically approved
Mitran, B., Thisgaard, H., Rosenström, U., Dam, J. H., Larhed, M., Tolmachev, V. & Orlova, A. (2017). High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM26. Contrast Media & Molecular Imaging, Article ID UNSP 6873684.
Open this publication in new window or tab >>High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM26
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2017 (English)In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, article id UNSP 6873684Article in journal (Refereed) Published
Abstract [en]

High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a Co-55-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with Co-57 and Co-55, stability, binding specificity, and in vitro and in vivo characteristics of Co-57-NOTA-PEG(2)-RM26 were studied. NOTA-PEG(2)-RM26 was successfully radiolabeled with Co-57 and Co-55 with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. Co-57-NOTA-PEG(2)-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG(2)-RM26 translated into high contrast preclinical PET/CT (using Co-55) and SPECT/CT (using Co-57) images of PC-3 xenografts. The initial biological results suggest that Co-55-NOTA-PEG(2)-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.

Keywords
Positron-Emission-Tomography, Receptor-Positive Tumors, In-Vivo Evaluation, Radiolabeled Peptides, Analog; Agonists, Visualization, Proteins, Affinity, Therapy.
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-334114 (URN)10.1155/2017/6873684 (DOI)000408099300001 ()
Funder
Swedish Cancer Society, CAN2014/474; CAN2015/350Swedish Research Council, 2015-02509; 2015-02353Knut and Alice Wallenberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2017-11-24Bibliographically approved
Bass, T. Z., Rosestedt, M., Mitran, B., Frejd, F. Y., Löfblom, J., Tolmachev, V., . . . Orlova, A. (2017). In vivo evaluation of a novel format of a bivalent HER3-targeting and albumin- binding therapeutic affibody construct. Scientific Reports, 7, Article ID 43118.
Open this publication in new window or tab >>In vivo evaluation of a novel format of a bivalent HER3-targeting and albumin- binding therapeutic affibody construct
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43118Article in journal (Refereed) Published
Abstract [en]

Overexpression of human epidermal growth factor receptor 3 (HER3) is involved in resistance to several therapies for malignant tumours. Currently, several anti-HER3 monoclonal antibodies are under clinical development. We introduce an alternative approach to HER3-targeted therapy based on engineered scaffold proteins, i.e. affibody molecules. We designed a small construct (22.5 kDa, denoted 3A3), consisting of two high-affinity anti-HER3 affibody molecules flanking an albumin-binding domain ABD, which was introduced for prolonged residence in circulation. In vitro, 3A3 efficiently inhibited growth of HER3-expressing BxPC-3 cells. Biodistribution in mice was measured using 3A3 that was site-specifically labelled with In-111 via a DOTA chelator. The residence time of In-111-DOTA-3A3 in blood was extended when compared with the monomeric affibody molecule. In-111-DOTA-3A3 accumulated specifically in HER3-expressing BxPC-3 xenografts in mice. However, In-111-DOTA-3A3 cleared more rapidly from blood than a size-matched control construct In-111-DOTA-TAT, most likely due to sequestering of 3A3 by mErbB3, the murine counterpart of HER3. Repeated dosing and increase of injected protein dose decreased uptake of In-111-DOTA-3A3 in mErbB3-expressing tissues. Encouragingly, growth of BxPC-3 xenografts in mice was delayed in an experimental (pilot-scale) therapy study using 3A3. We conclude that the 3A3 affibody format seems promising for treatment of HER3-overexpressing tumours.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-318958 (URN)10.1038/srep43118 (DOI)000394748000001 ()28230065 (PubMedID)
Funder
Swedish Cancer Society, CAN2013-586, CAN 2016/463, CAN2014-474, CAN2015/350Swedish Research Council, Swedish Research Council 621-2012-5236, 2015-02509, 2015-02353VINNOVA, 2016-04060
Available from: 2017-03-30 Created: 2017-03-30 Last updated: 2017-11-29Bibliographically approved
Garousi, J., Andersson, K. G., Dam, J. H., Olsen, B. B., Mitran, B., Orlova, A., . . . Tolmachev, V. (2017). The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule. Scientific Reports, 7, Article ID 5961.
Open this publication in new window or tab >>The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 5961Article in journal (Refereed) Published
Abstract [en]

Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The In-111-labelled DOTA-conjugated Z(EGFR:2377) Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-Z(EGFR:2377). DOTA-Z(EGFR:2377) was labelled with Co-57 (T-1/2 = 271.8 d), Co-55 (T-1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide Ga-68 (T-1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope Co-57 was used in animal studies. Both Co-57-DOTA-Z(EGFR:2377) and Ga-68-DOTA-Z(EGFR:2377) demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-Z(EGFR:2377) were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, Co-57-DOTA-Z(EGFR:2377) demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for (68)GaDOTA-Z(EGFR:2377). The results of this study suggest that the positron-emitting cobalt isotope 55Co would be an optimal label for DOTA-Z(EGFR:2377) and further development should concentrate on this radionuclide as a label.

Keywords
Epidermal-Growth-Factor; Factor Receptor Expression; Cell Lung-Cancer; Monoclonal-Antibody; Integrin Expression; Somatostatin Analog; Quantitative Pet; Positive Tumors; Carcinoma; Head
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-334098 (URN)10.1038/s41598-017-05700-7 (DOI)000405907800015 ()28729680 (PubMedID)
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2018-01-13Bibliographically approved
Sandström, M., Lindskog, K., Velikyan, I., Wennborg, A., Feldwisch, J., Sandberg, D., . . . Lubberink, M. (2016). Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients. Journal of Nuclear Medicine, 57(6), 867-871
Open this publication in new window or tab >>Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients
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2016 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 6, p. 867-871Article in journal (Refereed) Published
Abstract [en]

Ga-68-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of Ga-68-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD Ga-68-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 +/- 0.003 mSv/MBq for LD and 0.028 +/- 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of Ga-68-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other Ga-68-labeled tracers, such as 0.021 +/- 0.003 mSv/MBq for Ga-68-DOTATATE and Ga-68-DOTATOC, mainly because of higher uptake in liver and kidney.

Keywords
Affibody, breast cancer metastases, dosimetry, HER2-receptor, Ga-68-gallium
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-298861 (URN)10.2967/jnumed.115.169342 (DOI)000377052400035 ()26912439 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2017-11-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6120-2683

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