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55. [ 225 Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [ 225 Ac]Ac-PSMA-617.

Author

Busslinger, Sarah D., Tschan, Viviane J., Richard, Olivia K., Talip, Zeynep, Schibli, Roger, and Müller, Cristina

Subjects
STATISTICS, ANALYSIS of variance, ANIMAL experimentation, LOG-rank test, CELL receptors, TREATMENT effectiveness, DESCRIPTIVE statistics, KAPLAN-Meier estimator, PROSTATE-specific membrane antigen, MOLECULAR structure, DATA analysis software, DATA analysis, PROSTATE tumors, LIGANDS (Biochemistry), MICE, EVALUATION
Abstract

Simple Summary: Prostate-specific membrane antigen (PSMA) radioligands have proven effective to treat patients with metastatic castration-resistant prostate cancer. Targeted α-therapy using actinium-225 has been used for patients with end-stage disease who no longer responded to βࢤ-therapy through the use of 177Lu-based radioligand therapy (RLT). In this study, we investigated and compared the therapeutic efficacy of [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 and assessed potential undesired side effects in the preclinical setting. Due to a dedicated albumin-binding entity integrated into [225Ac]Ac-SibuDAB, this radioligand showed an enhanced blood circulation time and, hence, increased tumor uptake but also higher retention in normal tissues. The therapeutic efficacy of [225Ac]Ac-SibuDAB was enhanced as compared to that of [225Ac]Ac-PSMA-617, yet, undesired side effects were in the same range for both radioligands. Our data suggest that [225Ac]Ac-SibuDAB could be a powerful alternative to [225Ac]Ac-PSMA-617, however, the safe therapeutic window should be carefully defined in clinical dose escalation studies. In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer. [ABSTRACT FROM AUTHOR]

Published
2022
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59. Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Author

Borgna, Francesca, primary, Haller, Stephanie, additional, Rodriguez, Josep M. Monné, additional, Ginj, Mihaela, additional, Grundler, Pascal V., additional, Zeevaart, Jan Rijn, additional, Köster, Ulli, additional, Schibli, Roger, additional, van der Meulen, Nicholas P., additional, and Müller, Cristina, additional

Published
2021
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63. Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer.

Author

Tschan, Viviane J., Borgna, Francesca, Busslinger, Sarah D., Stirn, Martina, Rodriguez, Josep M. Monné, Bernhardt, Peter, Schibli, Roger, and Müller, Cristina

Subjects
PROSTATE cancer, CANCER treatment, TUMOR growth, TREATMENT effectiveness
Abstract

[177Lu]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [177Lu]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [177Lu]Lu-PSMA-617 and the previously developed [177Lu]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands's therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [177Lu]Lu-Ibu-DAB-PSMA (~ 6.6 Gy/MBq) was more effective to inhibit tumor growth than [177Lu]Lu-PSMA-617 (~ 4.5 Gy/MBq) and only moderately less potent than [177Lu]Lu-PSMA-ALB-56 (~ 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [177Lu]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [177Lu]Lu-Ibu-DAB-PSMA or [177Lu]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [177Lu]Lu-Ibu-DAB-PSMA or 30 MBq [177Lu]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [177Lu]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [177Lu]Lu-Ibu-DAB-PSMA over [177Lu]Lu-PSMA-617 and a more favorable safety profile as compared to that of [177Lu]Lu-PSMA-ALB-56. Based on these results, [177Lu]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation. [ABSTRACT FROM AUTHOR]

Published
2022
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65. Production of Mass-Separated Erbium-169 Towards the First Preclinical in vitro Investigations

Author

Talip, Zeynep, Borgna, Francesca, Müller, Cristina, Schibli, Roger, and van der Meulen, Nicholas P.

Subjects
in vitro studies, electromagnetic isotope separation, lanthanide-separation, activity standardization, laser resonance ionization, Er-169
Abstract

The β−-particle-emitting erbium-169 is a potential radionuclide toward therapy of metastasized cancer diseases. It can be produced in nuclear research reactors, irradiating isotopically-enriched 168Er2O3. This path, however, is not suitable for receptor-targeted radionuclide therapy, where high specific molar activities are required. In this study, an electromagnetic isotope separation technique was applied after neutron irradiation to boost the specific activity by separating 169Er from 168Er targets. The separation efficiency increased up to 0.5% using resonant laser ionization. A subsequent chemical purification process was developed as well as activity standardization of the radionuclidically pure 169Er. The quality of the 169Er product permitted radiolabeling and pre-clinical studies. A preliminary in vitro experiment was accomplished, using a 169Er-PSMA-617, to show the potential of 169Er to reduce tumor cell viability., Frontiers in Medicine, 8, ISSN:2296-858X

Published
2021

67. Terbium-149 for targeted alpha therapy

Author

Borgna, Francesca, Favaretto, Chiara, Grundler, Pascal, Johnston, Karl, Köster, Ulli, Müller, Cristina, Talip, Zeynep, and van der Meulen, Nick

Subjects
Detectors and Experimental Techniques
Published
2021

72. First-in-Humans Application of 161Tb: A Feasibility Study Using 161Tb-DOTATOC

Author

Baum, Richard P., primary, Singh, Aviral, additional, Kulkarni, Harshad R., additional, Bernhardt, Peter, additional, Rydén, Tobias, additional, Schuchardt, Christiane, additional, Gracheva, Nadezda, additional, Grundler, Pascal V., additional, Köster, Ulli, additional, Müller, Dirk, additional, Pröhl, Michael, additional, Zeevaart, Jan Rijn, additional, Schibli, Roger, additional, van der Meulen, Nicholas P., additional, and Müller, Cristina, additional

Published
2021
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76. Graphene: Insights on Biological, Radiochemical and Ecotoxicological Aspects

Author

Haixia, Xing, primary, de Barros, Aline Oliveira da Silva, additional, e Mello, Francisco do Vale Chaves, additional, Sozzi-Guo, Fan, additional, Müller, Cristina, additional, Gemini-Piperni, Sara, additional, Alencar, Luciana Magalhães Rebelo, additional, Maia, Francisco Franciné, additional, Freire, Valder Nogueira, additional, de Menezes, Frederico Duarte, additional, Aran, Veronica, additional, Devalle, Sylvie, additional, Moura-Neto, Vivaldo, additional, Ricci-Junior, Eduardo, additional, Bouskela, Eliete, additional, Pikula, Konstantin, additional, Golokhvast, Kirill, additional, and Santos-Oliveira, Ralph, additional

Published
2021
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80. Activity standardisation of 161Tb

Author

Nedjadi, Youcef, primary, Juget, Frédéric, additional, Desorgher, Laurent, additional, Durán, M. Teresa, additional, Bochud, François, additional, Müller, Cristina, additional, Talip, Zeynep, additional, van der Meulen, Nicholas P., additional, and Bailat, Claude, additional

Published
2020
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81. In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs

Author

Schniering, Janine, Borgna, Francesca, Siwowska, Klaudia, Benešová, Martina, Cohrs, Susan, Hasler, Roger, van der Meulen, Nicholas P, Maurer, Britta, Schibli, Roger, Müller, Cristina, University of Zurich, and Müller, Cristina

Subjects
1313 Molecular Medicine, 3002 Drug Discovery, 10051 Rheumatology Clinic and Institute of Physical Medicine, 3003 Pharmaceutical Science, 610 Medicine & health
Published
2018

84. Additional file 4 of Radiation dosimetry of 18F-AzaFol: A first in-human use of a folate receptor PET tracer

Author

Gnesin, Silvano, Müller, Joachim, Burger, Irene A., Meisel, Alexander, Siano, Marco, Früh, Martin, Choschzick, Matthias, Müller, Cristina, Schibli, Roger, Ametamey, Simon M., Kaufmann, Philipp A., Treyer, Valerie, Prior, John O., and Schaefer, Niklaus

Abstract

Additional file 4: Figure S4. Patient MIP images at 60 min using the same SUV scale for all images (0–5 g/mL).

Published
2020
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85. Additional file 6 of Radiation dosimetry of 18F-AzaFol: A first in-human use of a folate receptor PET tracer

Author

Gnesin, Silvano, Müller, Joachim, Burger, Irene A., Meisel, Alexander, Siano, Marco, Früh, Martin, Choschzick, Matthias, Müller, Cristina, Schibli, Roger, Ametamey, Simon M., Kaufmann, Philipp A., Treyer, Valerie, Prior, John O., and Schaefer, Niklaus

Abstract

Additional file 6: Figure S6. Time-activity curves (TAC), %IA/g and %IA/g corrected for 18F physical decay for all tumor analyzed (T#). In bracket, we indicated the patient identifier (P#).

Published
2020
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86. Additional file 1 of Radiation dosimetry of 18F-AzaFol: A first in-human use of a folate receptor PET tracer

Author

Gnesin, Silvano, Müller, Joachim, Burger, Irene A., Meisel, Alexander, Siano, Marco, Früh, Martin, Choschzick, Matthias, Müller, Cristina, Schibli, Roger, Ametamey, Simon M., Kaufmann, Philipp A., Treyer, Valerie, Prior, John O., and Schaefer, Niklaus

Abstract

Additional file 1: Figure S1. Segmented VOI obtained with PMOD software co-registered on the CT of the patient represented in Figure 1.

Published
2020
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89. First clinico-pathological evidence of a non PSMA-related uptake mechanism for 68Ga-PSMA-11 in salivary glands

Author

Rupp, Niels J, Umbricht, Christoph A, Pizzuto, Daniele A, Lenggenhager, Daniela, Töpfer, Antonia, Müller, Julian, Mühlematter, Urs Jacob, Ferraro, Daniela A, Messerli, Michael, Morand, Grégoire B, Huber, Gerhard F, Eberli, Daniel, Schibli, Roger, Müller, Cristina, Burger, Irene A, University of Zurich, and Burger, Irene A

Subjects
immuno, Prostate cancer, Specific Membrane Antigen, Prostate, 610 Medicine & health, 10045 Clinic for Otorhinolaryngology, 10181 Clinic for Nuclear Medicine, 177Lu, autoradiography, 68Ga, 10062 Urological Clinic, histochemistry, 10049 Institute of Pathology and Molecular Pathology, PSMA, 2741 Radiology, Nuclear Medicine and Imaging, Radiology Nuclear Medicine and Imaging, Positron Emission Tomography
Published
2019

98. Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC

Author

Kramer, Vasko, primary, Fernández, René, additional, Lehnert, Wencke, additional, Jiménez-Franco, Luis David, additional, Soza-Ried, Cristian, additional, Eppard, Elisabeth, additional, Ceballos, Matias, additional, Meckel, Marian, additional, Benešová, Martina, additional, Umbricht, Christoph A., additional, Kluge, Andreas, additional, Schibli, Roger, additional, Zhernosekov, Konstantin, additional, Amaral, Horacio, additional, and Müller, Cristina, additional

Published
2020
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