6 results on '"Haller, Stephanie"'
Search Results
2. Evaluation of the first 44 Sc-labeled Affibody molecule for imaging of HER2-expressing tumors.
- Author
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Honarvar H, Müller C, Cohrs S, Haller S, Westerlund K, Karlström AE, van der Meulen NP, Schibli R, and Tolmachev V
- Subjects
- Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Humans, Isotope Labeling, Mice, Tissue Distribution, Gene Expression Regulation, Neoplastic, Positron-Emission Tomography methods, Radioisotopes, Receptor, ErbB-2 metabolism, Recombinant Proteins pharmacokinetics, Scandium
- Abstract
Introduction: Affibody molecules are small (58 amino acids) high-affinity proteins based on a tri-helix non-immunoglobulin scaffold. A clinical study has demonstrated that PET imaging using Affibody molecules labeled with
68 Ga (T½ =68min) can visualize metastases of breast cancer expressing human epidermal growth factor receptor type 2 (HER2) and provide discrimination between tumors with high and low expression level. This may help to identify breast cancer patients benefiting from HER2-targeting therapies. The best discrimination was at 4h post injection. Due to longer half-life, a positron-emitting radionuclide44 Sc (T½ =4.04h) might be a preferable label for Affibody molecules for imaging at several hours after injection., Methods: A synthetic second-generation anti-HER2 Affibody molecule ZHER2:2891 was labeled with44 Sc via a DOTA-chelator conjugated to the N-terminal amino group. Binding specificity, affinity and cellular processing44 Sc-DOTA-ZHER2:2891 and68 Ga-DOTA-ZHER2:2891 were compared in vitro using HER2-expressing cells. Biodistribution and imaging properties of44 Sc-DOTA-ZHER2:2891 and68 Ga-DOTA-ZHER2:2891 were evaluated in Balb/c nude mice bearing HER2-expression xenografts., Results: The labeling yield of 98±2% and specific activity of 7.8GBq/μmol were obtained. The conjugate demonstrated specific binding to HER2-expressing SKOV3.ip cells in vitro and to SKOV3.ip xenografts in nude mice. The distribution of radioactivity at 3h post injection was similar for44 Sc-DOTA-ZHER2:2891 and68 Ga-DOTA-ZHER2:2891 , but the blood clearance of the44 Sc-labeled variant was slower and the tumor-to-blood ratio was reduced (15±2 for44 Sc-DOTA-ZHER2:2891 vs 46±9 for68 Ga-DOTA-ZHER2:2891 ). At 6h after injection of44 Sc-DOTA-ZHER2:2891 the tumor uptake was 8±2% IA/g and the tumor-to-blood ratio was 51±8. Imaging using small-animal PET/CT demonstrated that44 Sc-DOTA-ZHER2:2891 provides specific and high-contrast imaging of HER2-expressing xenografts., Conclusion: The44 Sc- DOTA-ZHER2:2891 Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2017
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3. Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy.
- Author
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Haller S, Reber J, Brandt S, Bernhardt P, Groehn V, Schibli R, and Müller C
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- Animals, Biological Transport radiation effects, Body Weight radiation effects, Cell Survival radiation effects, Coordination Complexes pharmacokinetics, Coordination Complexes therapeutic use, Female, Folic Acid analogs & derivatives, Folic Acid pharmacokinetics, Folic Acid therapeutic use, Humans, KB Cells, Kidney metabolism, Kidney pathology, Kidney radiation effects, Leukocytes cytology, Leukocytes radiation effects, Mice, Mice, Nude, Neoplasms blood, Neoplasms metabolism, Radiometry, Radiopharmaceuticals pharmacokinetics, Survival Analysis, Technetium Tc 99m Dimercaptosuccinic Acid metabolism, Coordination Complexes adverse effects, Folic Acid adverse effects, Folic Acid Transporters metabolism, Kidney Diseases etiology, Neoplasms radiotherapy, Radiation Injuries etiology, Radiopharmaceuticals adverse effects, Radiopharmaceuticals therapeutic use
- Abstract
Introduction: Application of therapeutic folate radioconjugates is a promising option for the treatment of folate receptor (FR)-positive tumors, although high uptake of radiofolates in the kidneys remains a critical issue. Recently, it was shown that enhancing the blood circulation of radiofolates results in increased tumor uptake and reduced retention of radioactivity in the kidneys. In this study, we investigated and compared the anti-tumor effects and potential long-term damage to the kidneys after application of an albumin-binding ((177)Lu-cm09), and a conventional ((177)Lu-EC0800) folate radioconjugate., Methods: In vivo studies were performed with KB tumor-bearing nude mice. (177)Lu-EC0800 and (177)Lu-cm09 were applied at variable quantities (10-30 MBq/mouse), and the tumor growth was monitored over time. Mice without tumors were injected with the same radiofolates and investigated over eight months by determination of creatinine and blood urea nitrogen plasma levels and by measuring renal uptake of (99m)Tc-DMSA using SPECT. At the study end, the morphological changes were examined on renal tissue sections using variable staining methods., Results: Compared to untreated controls, dose-dependent tumor growth inhibition and prolonged survival was observed in all treated mice. In line with the resulting absorbed dose, the treatment was more effective with (177)Lu-cm09 than with (177)Lu-EC0800, enabling complete tumor remission after application of ≥20MBq (≥28Gy). Application of radiofolates with an absorbed renal dose ≥23 Gy showed increased levels of renal plasma parameters and reduced renal uptake of (99m)Tc-DSMA. Morphological changes observed on tissue sections confirmed radionephropathy of variable stages., Conclusions: (177)Lu-cm09 showed more favorable anti-tumor effects and significantly less damage to the kidneys compared to (177)Lu-EC0800 as was expected based on improved tumor-to-kidney ratios. It was demonstrated that enhancing the blood circulation time of radiofolates was favorable regarding the risk-benefit profile of a therapeutic application. These results hold promise for future translation of the albumin-binder concept to the clinics, potentially enabling FR-targeted radionuclide therapy in patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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4. Cyclotron production of (44)Sc: From bench to bedside.
- Author
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van der Meulen NP, Bunka M, Domnanich KA, Müller C, Haller S, Vermeulen C, Türler A, and Schibli R
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- Computer Graphics, Computer Simulation, Image Enhancement methods, Machine Learning, Models, Biological, Models, Statistical, Numerical Analysis, Computer-Assisted, Reproducibility of Results, Sensitivity and Specificity, Signal Processing, Computer-Assisted, User-Computer Interface, Algorithms, Image Interpretation, Computer-Assisted methods, Imaging, Three-Dimensional methods, Information Storage and Retrieval methods, Multimodal Imaging methods, Pattern Recognition, Automated methods, Subtraction Technique
- Abstract
Introduction: (44)Sc, a PET radionuclide, has promising decay characteristics (T1/2 = 3.97 h, Eβ(+)av = 632 keV) for nuclear imaging and is an attractive alternative to the short-lived (68)Ga (T1/2 = 68 min, Eβ(+)av = 830 keV). The aim of this study was the optimization of the (44)Sc production process at an accelerator, allowing its use for preclinical and clinical PET imaging., Methods: (44)CaCO3 targets were prepared and irradiated with protons (~11 MeV) at a beam current of 50 μA for 90 min. (44)Sc was separated from its target material using DGA extraction resin and concentrated using SCX cation exchange resin. Radiolabeling experiments at activities up to 500 MBq and stability tests were performed with DOTANOC by investigating different scavengers, including gentisic acid. Dynamic PET of an AR42J tumor-bearing mouse was performed after injection of (44)Sc-DOTANOC., Results: The optimized chemical separation method yielded up to 2 GBq (44)Sc of high radionuclidic purity. In the presence of gentisic acid, radiolabeling of (44)Sc with DOTANOC was achieved with a radiochemical yield of ~99% at high specific activity (10 MBq/nmol) and quantities which would allow clinical application. The dynamic PET images visualized increasing uptake of (44)Sc-DOTANOC into AR42J tumors and excretion of radioactivity through the kidneys of the investigated mouse., Conclusions: The concept "from-bench-to-bedside" was clearly demonstrated in this extended study using cyclotron-produced (44)Sc. Sufficiently high activities of (44)Sc of excellent radionuclidic purity are obtainable for clinical application, by irradiation of enriched calcium at a cyclotron. This work demonstrates a promising basis for introducing (44)Sc to clinical routine of nuclear imaging using PET., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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5. Investigation of the chick embryo as a potential alternative to the mouse for evaluation of radiopharmaceuticals.
- Author
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Haller S, Ametamey SM, Schibli R, and Müller C
- Subjects
- Animals, Bone and Bones diagnostic imaging, Bone and Bones metabolism, Feasibility Studies, Mice, Positron-Emission Tomography, Species Specificity, Thyroid Gland diagnostic imaging, Tissue Distribution, Tomography, Emission-Computed, Single-Photon, Chick Embryo, Radiopharmaceuticals pharmacokinetics
- Abstract
Introduction: The chick embryo is an emerging in vivo model in several areas of pre-clinical research including radiopharmaceutical sciences. Herein, it was evaluated as a potential test system for assessing the biodistribution and in vivo stability of radiopharmaceuticals. For this purpose, a number of radiopharmaceuticals labeled with (18)F, (125)I, (99m)Tc, and (177)Lu were investigated in the chick embryo and compared with the data obtained in mice., Methods: Chick embryos were cultivated ex ovo for 17-19 days before application of the radiopharmaceutical directly into the peritoneum or intravenously using a vein of the chorioallantoic membrane (CAM). At a defined time point after application of radioactivity, the embryos were euthanized by shock-freezing using liquid nitrogen. Afterwards they were separated from residual egg components for post mortem imaging purposes using positron emission tomography (PET) or single photon emission computed tomography (SPECT)., Results: SPECT images revealed uptake of [(99m)Tc]pertechnetate and [(125)I]iodide in the thyroid of chick embryos and mice, whereas [(177)Lu]lutetium, [(18)F]fluoride and [(99m)Tc]-methylene diphosphonate ([(99m)Tc]-MDP) were accumulated in the bones. [(99m)Tc]-dimercaptosuccinic acid ((99m)Tc-DMSA) and the somatostatin analog [(177)Lu]-DOTATOC, as well as the folic acid derivative [(177)Lu]-DOTA-folate showed accumulation in the renal tissue whereas [(99m)Tc]-mebrofenin accumulated in the gall bladder and intestine of both species. In vivo dehalogenation of [(18)F]fallypride and of the folic acid derivative [(125)I]iodo-tyrosine-folate was observed in both species. In contrast, the 3'-aza-2'-[(18)F]fluorofolic acid ([(18)F]-AzaFol) was stable in the chick embryo as well as in the mouse., Conclusions: Our results revealed the same tissue distribution profile and in vivo stability of radiopharmaceuticals in the chick embryo and the mouse. This observation is promising with regard to a potential use of the chick embryo as an inexpensive and simple test model for preclinical screening of novel radiopharmaceuticals., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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6. Future prospects for SPECT imaging using the radiolanthanide terbium-155 - production and preclinical evaluation in tumor-bearing mice.
- Author
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Müller C, Fischer E, Behe M, Köster U, Dorrer H, Reber J, Haller S, Cohrs S, Blanc A, Grünberg J, Bunka M, Zhernosekov K, van der Meulen N, Johnston K, Türler A, and Schibli R
- Subjects
- Animals, Female, Half-Life, Humans, KB Cells, Mice, Octreotide chemistry, Terbium pharmacokinetics, Tomography, X-Ray Computed, Radiochemistry, Radioisotopes, Terbium chemistry, Tomography, Emission-Computed, Single-Photon methods
- Abstract
Introduction: We assessed the suitability of the radiolanthanide (155)Tb (t1/2=5.32 days, Eγ=87 keV (32%), 105keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging., Methods: (155)Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. (155)Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules - a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) - were radiolabeled with (155)Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner., Results: The total yield of the two-step separation process of (155)Tb was 86%. (155)Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The (155)Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (>95%). (155)Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of (155)Tb-DOTATATE and (155)Tb-MD, respectively. The relatively long physical half-life of (155)Tb matched in particular the biological half-lives of (155)Tb-cm09 and (155)Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration., Conclusions: The radiolanthanide (155)Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β(-)-emitting radiolanthanides (177)Lu, (161)Tb, (166)Ho, and the pseudo-radiolanthanide (90)Y., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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