17 results on '"Müller, Cristina"'
Search Results
2. Alpha-PET for Prostate Cancer: Preclinical investigation using 149 Tb-PSMA-617.
- Author
-
Umbricht CA, Köster U, Bernhardt P, Gracheva N, Johnston K, Schibli R, van der Meulen NP, and Müller C
- Subjects
- Animals, Antigens, Surface genetics, Antigens, Surface metabolism, Glutamate Carboxypeptidase II genetics, Glutamate Carboxypeptidase II metabolism, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, PC-3 Cells, Prostate-Specific Antigen, Staining and Labeling, Tissue Distribution, Transduction, Genetic, Treatment Outcome, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Dipeptides pharmacokinetics, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring pharmacokinetics, Heterocyclic Compounds, 1-Ring therapeutic use, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms drug therapy, Radioisotopes pharmacokinetics, Terbium pharmacokinetics
- Abstract
In this study, it was aimed to investigate
149 Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer.149 Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors.149 Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Day 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia. The tumor growth was significantly delayed in mice of the treated groups as compared to untreated controls (p < 0.05). TAT was most effective in mice injected with 2 × 3 MBq (Day 0 & 1) resulting in a median lifetime of 36 days, whereas in untreated mice, the median lifetime was only 20 days. Due to the β+ -emission of149 Tb, tumor localization was feasible using PET/CT after injection of149 Tb-PSMA-617 (5 MBq). The PET images confirmed the selective accumulation of149 Tb-PSMA-617 in PC-3 PIP tumor xenografts. The unique characteristics of149 Tb for TAT make this radionuclide of particular interest for future clinical translation, thereby, potentially enabling PET-based imaging to monitor the radioligand's tissue distribution.- Published
- 2019
- Full Text
- View/download PDF
3. Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer.
- Author
-
Müller C, Umbricht CA, Gracheva N, Tschan VJ, Pellegrini G, Bernhardt P, Zeevaart JR, Köster U, Schibli R, and van der Meulen NP
- Subjects
- Animals, Cell Proliferation radiation effects, Cell Survival radiation effects, Dipeptides pharmacokinetics, Heterocyclic Compounds, 1-Ring pharmacokinetics, Humans, Male, Mice, PC-3 Cells, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Single Photon Emission Computed Tomography Computed Tomography, Tissue Distribution, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Prostatic Neoplasms, Castration-Resistant radiotherapy, Radioisotopes therapeutic use, Terbium therapeutic use
- Abstract
Purpose: The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate
161 Tb (T1/2 = 6.89 days; Eβ͞ av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to177 Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile., Methods:161 Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol.161 Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for177 Lu-PSMA-617. The effects of161 Tb-PSMA-617 and177 Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells.161 Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice., Results:161 Tb-PSMA-617 and177 Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to161 Tb-PSMA-617 as compared to the effect obtained with the same activities of177 Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with161 Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of161 Tb-PSMA-617 and177 Lu-PSMA-617 indicated the anticipated superiority of161 Tb over177 Lu., Conclusion:161 Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to177 Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of161 Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of161 Tb-PSMA-617 for the treatment of mCRPC.- Published
- 2019
- Full Text
- View/download PDF
4. Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application.
- Author
-
Müller C, Domnanich KA, Umbricht CA, and van der Meulen NP
- Subjects
- Clinical Trials as Topic, Half-Life, Humans, Positron-Emission Tomography methods, Positron-Emission Tomography trends, Technology, Radiologic methods, Technology, Radiologic trends, Theranostic Nanomedicine trends, Tomography, Emission-Computed, Single-Photon methods, Tomography, Emission-Computed, Single-Photon trends, Radioisotopes, Radiopharmaceuticals, Scandium, Terbium, Theranostic Nanomedicine methods
- Abstract
Currently, different radiometals are in use for imaging and therapy in nuclear medicine:
68 Ga and111 In are examples of nuclides for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, while177 Lu and225 Ac are used for β- - and α-radionuclide therapy. The application of diagnostic and therapeutic radionuclides of the same element (radioisotopes) would utilize chemically-identical radiopharmaceuticals for imaging and subsequent treatment, thereby enabling the radiotheranostic concept. There are two elements which are of particular interest in this regard: Scandium and Terbium. Scandium presents three radioisotopes for theranostic application.43 Sc (T1/2 = 3.9 h) and44 Sc (T1/2 = 4.0 h) can both be used for PET, while47 Sc (T1/2 = 3.35 d) is the therapeutic match-also suitable for SPECT. Currently,44 Sc is most advanced in terms of production, as well as with pre-clinical investigations, and has already been employed in proof-of-concept studies in patients. Even though the production of43 Sc may be more challenging, it would be advantageous due to the absence of high-energetic γ-ray emission. The development of47 Sc is still in its infancy, however, its therapeutic potential has been demonstrated preclinically. Terbium is unique in that it represents four medically-interesting radioisotopes.155 Tb (T1/2 = 5.32 d) and152 Tb (T1/2 = 17.5 h) can be used for SPECT and PET, respectively. Both radioisotopes were produced and tested preclinically.152 Tb has been the first Tb isotope that was tested (as152 Tb-DOTATOC) in a patient. Both radionuclides may be of interest for dosimetry purposes prior to the application of radiolanthanide therapy. The decay properties of161 Tb (T1/2 = 6.89 d) are similar to177 Lu, but the coemission of Auger electrons make it attractive for a combined β- /Auger electron therapy, which was shown to be effective in preclinical experiments.149 Tb (T1/2 = 4.1 h) has been proposed for targeted α-therapy with the possibility of PET imaging. In terms of production,161 Tb and155 Tb are most promising to be made available at the large quantities suitable for future clinical translation. This review article is dedicated to the production routes, the methods of separating the radioisotopes from the target material, preclinical investigations and clinical proof-of-concept studies of Sc and Tb radionuclides. The availability, challenges of production and first (pre)clinical application, as well as the potential of these novel radionuclides for future application in nuclear medicine, are discussed.- Published
- 2018
- Full Text
- View/download PDF
5. Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with 152 Tb-DOTATOC.
- Author
-
Baum RP, Singh A, Benešová M, Vermeulen C, Gnesin S, Köster U, Johnston K, Müller D, Senftleben S, Kulkarni HR, Türler A, Schibli R, Prior JO, van der Meulen NP, and Müller C
- Subjects
- Aged, Humans, Isotope Labeling, Male, Neuroendocrine Tumors diagnostic imaging, Octreotide chemistry, Phantoms, Imaging, Radiochemistry, Octreotide analogs & derivatives, Positron Emission Tomography Computed Tomography methods, Radioisotopes chemistry, Terbium chemistry
- Abstract
The existence of theragnostic pairs of radionuclides allows the preparation of radiopharmaceuticals for diagnostic and therapeutic purposes. Radiolanthanides, such as
177 Lu, are successfully used for therapeutic purposes; however, a perfect diagnostic match is currently not available for clinical use. A unique, multi-disciplinary study was performed using152 Tb (T1/2 = 17.5 h, Eβ+ average = 1140 keV, Iβ+ = 20.3%), which resulted in the first-in-human PET/CT images with this promising radionuclide. For this purpose,152 Tb was produced via a spallation process followed by mass separation at ISOLDE, CERN. The chemical separation and quality control, performed at PSI, resulted in a pure product in sufficient yields. Clinical PET phantom studies revealed an increased image noise level, because of the smaller β+ branching ratio of152 Tb as compared to standard PET nuclides at matched activity concentrations; however, the expected recovery would be comparable at matched signal-to-noise ratios in clinical PET.152 Tb was used for labeling DOTATOC, at Zentralklinik Bad Berka, and administered to a patient for a first-in-human clinical study. PET scans were performed over a period of 24 h, allowing the visualization of even small metastases with increased tumor-to-background contrast over time. Based on the results obtained in this work, it can be deduced that PET/CT imaging with152 Tb-labeled targeting agents has promise for clinical application and may be particularly interesting for pre-therapeutic dosimetry.- Published
- 2017
- Full Text
- View/download PDF
6. Future prospects for SPECT imaging using the radiolanthanide terbium-155 - production and preclinical evaluation in tumor-bearing mice.
- Author
-
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
- Full Text
- View/download PDF
7. Direct in vitro and in vivo comparison of (161)Tb and (177)Lu using a tumour-targeting folate conjugate.
- Author
-
Müller C, Reber J, Haller S, Dorrer H, Bernhardt P, Zhernosekov K, Türler A, and Schibli R
- Subjects
- Animals, Coordination Complexes therapeutic use, Female, Folic Acid chemistry, Folic Acid therapeutic use, HeLa Cells, Humans, Lutetium chemistry, Lutetium therapeutic use, Mice, Mice, Nude, Neoplasms, Experimental diagnostic imaging, Neoplasms, Experimental radiotherapy, Radioisotopes chemistry, Radioisotopes pharmacokinetics, Radioisotopes therapeutic use, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals therapeutic use, Terbium chemistry, Terbium therapeutic use, Tomography, Emission-Computed, Single-Photon, Xenograft Model Antitumor Assays, Coordination Complexes pharmacokinetics, Folic Acid analogs & derivatives, Folic Acid pharmacokinetics, Lutetium pharmacokinetics, Radiopharmaceuticals pharmacokinetics, Terbium pharmacokinetics
- Abstract
Purpose: The radiolanthanide (161)Tb (T 1/2 = 6.90 days, Eβ(-) av = 154 keV) was recently proposed as a potential alternative to (177)Lu (T 1/2 = 6.71 days, Eβ(-) av = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare (161)Tb and (177)Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09)., Methods: (161)Tb-cm09 and (177)Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo (161)Tb-cm09 and (177)Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using (99m)Tc-dimercaptosuccinic acid (DMSA)., Results: To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for (161)Tb-cm09 (IC50 ~0.014 MBq/ml and ~2.53 MBq/ml) compared to (177)Lu-cm09 (IC50 ~0.063 MBq/ml and ~4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies (161)Tb-cm09 reduced tumour growth more efficiently than (177)Lu-cm09. These findings were in line with the higher absorbed tumour dose for (161)Tb-cm09 (3.3 Gy/MBq) compared to (177)Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates., Conclusion: Compared to (177)Lu-cm09 we demonstrated equal imaging features for (161)Tb-cm09 but an increased therapeutic efficacy for (161)Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of (161)Tb.
- Published
- 2014
- Full Text
- View/download PDF
8. A unique matched quadruplet of terbium radioisotopes for PET and SPECT and for α- and β- radionuclide therapy: an in vivo proof-of-concept study with a new receptor-targeted folate derivative.
- Author
-
Müller C, Zhernosekov K, Köster U, Johnston K, Dorrer H, Hohn A, van der Walt NT, Türler A, and Schibli R
- Subjects
- Alpha Particles therapeutic use, Animals, Beta Particles therapeutic use, Female, Folate Receptors, GPI-Anchored metabolism, Folic Acid chemistry, Folic Acid therapeutic use, Heterocyclic Compounds, 1-Ring chemistry, Humans, KB Cells, Mice, Folic Acid metabolism, Positron-Emission Tomography methods, Radioisotopes therapeutic use, Terbium therapeutic use, Tomography, Emission-Computed, Single-Photon methods
- Abstract
Unlabelled: Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: (149)Tb, (152)Tb, (155)Tb, and (161)Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET ((152)Tb) and SPECT diagnosis ((155)Tb) and for α- ((149)Tb) and β(-)-particle ((161)Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent., Methods: (161)Tb was produced by irradiation of (160)Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived (161)Gd decays to (161)Tb. (149)Tb, (152)Tb, and (155)Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA-folate conjugate cm09, which binds to folate receptor (FR)-positive KB tumor cells. Therapy experiments with (149)Tb-cm09 and (161)Tb-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/CT ((152)Tb-cm09) and SPECT/CT ((155)Tb-cm09 and (161)Tb-cm09) studies were performed in the same tumor mouse model., Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for (149)Tb) to approximately 15 MBq (for (161)Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% ± 2.5% at 4 h after injection, 22.0% ± 4.4% at 24 h after injection, and 18.4% ± 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ≈ 15; tumor to liver, ≈ 5.9; and tumor to kidney, ≈ 0.8) allowed the visualization of tumors in mice using PET ((152)Tb-cm09) and SPECT ((155)Tb-cm09 and (161)Tb-cm09). Compared with no therapy, α- ((149)Tb-cm09) and β(-)-particle therapy ((161)Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for (149)Tb-cm09 and 80% for (161)Tb-cm09) and a significantly increased survival., Conclusion: For the first time, to our knowledge, 4 terbium radionuclides have been tested in parallel with tumor-bearing mice using an FR targeting agent. Along with excellent tumor visualization enabled by (152)Tb PET and (155)Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter (149)Tb and β(-)-emitter (161)Tb.
- Published
- 2012
- Full Text
- View/download PDF
9. Terbium 'Sisters': More Than just a 'Swiss Army Knife'
- Author
-
Müller, Cristina, van der Meulen, Nicholas P., and Prasad, Vikas, editor
- Published
- 2024
- Full Text
- View/download PDF
10. Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer
- Author
-
Müller, Cristina, Singh, Aviral, Umbricht, Christoph A., Kulkarni, Harshad R., Johnston, Karl, Benešová, Martina, Senftleben, Stefan, Müller, Dirk, Vermeulen, Christiaan, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Baum, Richard P.
- Published
- 2019
- Full Text
- View/download PDF
11. Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms.
- Author
-
Borgna, Francesca, Haller, Stephanie, Rodriguez, Josep M. Monné, Ginj, Mihaela, Grundler, Pascal V., Zeevaart, Jan Rijn, Köster, Ulli, Schibli, Roger, van der Meulen, Nicholas P., and Müller, Cristina
- Subjects
NEUROENDOCRINE tumors ,TERBIUM ,AUGER electrons ,RADIOISOTOPES ,CANCER cells - Abstract
Purpose: The β
¯ -emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods: The capability of the161 Tb- and177 Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides' tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results: In vitro, [161 Tb]Tb-DOTA-LM3 was 102-fold more potent than [177 Lu]Lu-DOTA-LM3; however,161 Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their177 Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161 Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177 Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion: The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161 Tb]Tb-DOTA-LM3 may outperform the clinically employed [177 Lu]Lu-DOTATOC for the treatment of patients with NENs. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
12. Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with 152Tb-DOTATOC.
- Author
-
Baum, Richard P., Singh, Aviral, Benešová, Martina, Vermeulen, Christiaan, Gnesin, Silvano, Köster, Ulli, Johnston, Karl, Müller, Dirk, Senftleben, Stefan, Kulkarni, Harshad R., Türler, Andreas, Schibli, Roger, Prior, John O., van der Meulen, Nicholas P., and Müller, Cristina
- Subjects
TERBIUM ,RADIOISOTOPES ,RADIOPHARMACEUTICALS - Abstract
The existence of theragnostic pairs of radionuclides allows the preparation of radiopharmaceuticals for diagnostic and therapeutic purposes. Radiolanthanides, such as
177 Lu, are successfully used for therapeutic purposes; however, a perfect diagnostic match is currently not available for clinical use. A unique, multi-disciplinary study was performed using152 Tb (T1/2 = 17.5 h, Eβ+ average = 1140 keV, Iβ+ = 20.3%), which resulted in the first-in-human PET/CT images with this promising radionuclide. For this purpose,152 Tb was produced via a spallation process followed by mass separation at ISOLDE, CERN. The chemical separation and quality control, performed at PSI, resulted in a pure product in sufficient yields. Clinical PET phantom studies revealed an increased image noise level, because of the smaller β+ branching ratio of152 Tb as compared to standard PET nuclides at matched activity concentrations; however, the expected recovery would be comparable at matched signal-to-noise ratios in clinical PET.152 Tb was used for labeling DOTATOC, at Zentralklinik Bad Berka, and administered to a patient for a first-in-human clinical study. PET scans were performed over a period of 24 h, allowing the visualization of even small metastases with increased tumor-to-background contrast over time. Based on the results obtained in this work, it can be deduced that PET/CT imaging with152 Tb-labeled targeting agents has promise for clinical application and may be particularly interesting for pre-therapeutic dosimetry. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
13. Direct in vitro and in vivo comparison of Tb and Lu using a tumour-targeting folate conjugate.
- Author
-
Müller, Cristina, Reber, Josefine, Haller, Stephanie, Dorrer, Holger, Bernhardt, Peter, Zhernosekov, Konstantin, Türler, Andreas, and Schibli, Roger
- Subjects
AUGER electrons ,TERBIUM ,LUTETIUM ,CANCER cells ,PHOTON emission ,RADIOACTIVITY - Abstract
Purpose: The radiolanthanide Tb ( T = 6.90 days, Eβ = 154 keV) was recently proposed as a potential alternative to Lu ( T = 6.71 days, Eβ = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare Tb and Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). Methods: Tb-cm09 and Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo Tb-cm09 and Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using Tc-dimercaptosuccinic acid (DMSA). Results: To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for Tb-cm09 (IC ~0.014 MBq/ml and ~2.53 MBq/ml) compared to Lu-cm09 (IC ~0.063 MBq/ml and ~4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies Tb-cm09 reduced tumour growth more efficiently than Lu-cm09. These findings were in line with the higher absorbed tumour dose for Tb-cm09 (3.3 Gy/MBq) compared to Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Conclusion: Compared to Lu-cm09 we demonstrated equal imaging features for Tb-cm09 but an increased therapeutic efficacy for Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of Tb. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
14. Simultaneous Visualization of 161 Tb- and 177 Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging.
- Author
-
Borgna, Francesca, Barritt, Patrick, Grundler, Pascal V., Talip, Zeynep, Cohrs, Susan, Zeevaart, Jan Rijn, Köster, Ulli, Schibli, Roger, van der Meulen, Nicholas P., Müller, Cristina, and Seimbille, Yann
- Subjects
COMPUTED tomography ,SINGLE-photon emission computed tomography ,SOMATOSTATIN ,VISUALIZATION ,TERBIUM ,RADIOISOTOPES - Abstract
The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The
161 Tb- and177 Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of161 Tb- and177 Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
15. Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer.
- Author
-
Müller, Cristina, Singh, Aviral, Umbricht, Christoph A., Kulkarni, Harshad R., Johnston, Karl, Benešová, Martina, Senftleben, Stefan, Müller, Dirk, Vermeulen, Christiaan, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Baum, Richard P.
- Subjects
- *
POSITRON emission tomography computed tomography , *CASTRATION-resistant prostate cancer , *PROSTATE cancer , *IMAGING of cancer , *NUCLEAR medicine , *DIAGNOSTIC imaging - Abstract
Background: For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined β−/Auger-e−-therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). Results: 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. Conclusions: The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
16. Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer
- Author
-
Müller, Cristina, Singh, Aviral, Umbricht, Christoph A., Kulkarni, Harshad R., Johnston, Karl, Benešová, Martina, Senftleben, Stefan, Müller, Dirk, Vermeulen, Christiaan, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Baum, Richard P.
- Subjects
Prostate cancer ,PET/CT imaging ,Theragnostics ,152Tb ,Terbium ,PSMA-617 ,3. Good health - Abstract
Background For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined β−/Auger-e−-therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). Results 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. Conclusions The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients., EJNMMI Research, 9 (1), ISSN:2191-219X
17. Determination of 161Tb half-life by three measurement methods.
- Author
-
Durán, M. Teresa, Juget, Frédéric, Nedjadi, Youcef, Bochud, François, Grundler, Pascal V., Gracheva, Nadezda, Müller, Cristina, Talip, Zeynep, van der Meulen, Nicholas P., and Bailat, Claude
- Subjects
- *
DIGITAL electronics , *TERBIUM , *IONIZATION chambers , *ELECTRON emission , *TREATMENT effectiveness , *REFERENCE values - Abstract
The radiolanthanide 161Tb is being studied as an alternative to 177Lu for targeted radionuclide tumor therapy. Both β--particle emitters show similar chemical behavior and decay characteristics, but 161Tb delivers additional conversion and Auger electron emissions that may enhance the therapeutic efficacy. In this study, the half-life of 161Tb was determined by a combination of three independent measurement systems: reference ionization chamber (CIR, chambre d'ionization de référence), portable ionization chamber (TCIR) and a CeBr 3 γ-emission detector with digital electronics. The half-life determined for 161Tb is 6.953(2) days, showing a significant improvement in the uncertainty, which is one order of magnitude lower, with a deviation of 0.91% from the last nuclear data reference value. The previous large uncertainty of the half-life had a direct impact on activity measurements. Now it is no more an obstacle to a primary standardization. • The half-life obtained for 161-Tb is 6.953(2) days. • A deviation of 0.91% from the last nuclear data reference value is found. • The uncertainty is reduced by is one order of magnitude from reference value. • Stability, statistical robustness and uncertainty budget lead to an improved result. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.