Publications by authors named "Frank Bruchertseifer"

104 Publications

Radiochemical separation of Ra from U and Th sources for Ra/Pb/Bi generator.

Appl Radiat Isot 2021 Feb 25;172:109655. Epub 2021 Feb 25.

Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195, Warsaw, Poland. Electronic address:

The application of diagnostic and therapeutic radionuclides in nuclear medicine has grown significantly and has translated into the increased interest in radionuclide generators and their development. Ra and its shorter-lived daughters, Pb and Bi, are very interesting radionuclides from Targeted Alpha Therapy point of view for treatment of small cancers or metastatic forms. The purpose of the present work was to develop a simple generator for rapid elution of carrier-free Ra from U or Th sources by radiochemical separation based on extraction chromatography with the utilization of a home-made material. The bis(2-ethylhexyl) hydrogen phosphate (HDEHP) extractant was immobilized on polytetrafluroethylene (PTFE) grains and its ability to selectively adsorb U and Th, with simultaneous high elution recovery of Ra, was checked over few years. The Ra was quantitatively eluted with small volume (3-5 mL) of 0.1 M HNO with low breakthrough (<0.005%) and was used for further milking of Bi and Pb from DOWEX 50WX12 by 0.75 M and 2.0 M HCl, respectively. The elaborated here methods allowed high recovery of Ra, Pb and Bi radionuclides and their application in radiolabeling of various biomolecules.
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http://dx.doi.org/10.1016/j.apradiso.2021.109655DOI Listing
February 2021

Clinical outcomes and molecular profiling of advanced metastatic castration-resistant prostate cancer patients treated with Ac-PSMA-617 targeted alpha-radiation therapy.

Urol Oncol 2020 Dec 19. Epub 2020 Dec 19.

Radboud University Medical Center, Department of Medical Oncology, Nijmegen, The Netherlands.

Introduction: Targeted alpha-radiation therapy (TAT) with Ac-labeled prostate-specific membrane antigen (PSMA) ligands is a promising novel treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. However, limited data are available on efficacy, quality of life (QoL), and pretherapeutic biomarkers. The aim of this study was to evaluate the efficacy of Ac-PSMA TAT and impact on QoL in advanced mCRPC, and to explore predictive biomarkers on pretherapeutic metastatic tissue biopsies.

Methods: Observational cohort study including consecutive patients treated with Ac-PSMA TAT between February 2016 and July 2018. Primary endpoint was overall survival (OS). Furthermore, prostate-specific antigen (PSA) changes, radiological response, safety, QoL, and xerostomia were evaluated. Biopsies were analyzed with immunohistochemistry and next-generation sequencing.

Results: Thirteen patients were included. Median OS was 8.5 months for the total cohort and 12.6 months for PSMA radioligand therapy-naïve patients. PSA declines of ≥90% and ≥50% were observed in 46% and 69% of patients, respectively. Six patients were radiologically evaluable; 50% showed partial response. All patients showed >90% total tumor volume reduction on PET imaging. Patients experienced clinically relevant decrease of pain and QoL improvement in physical and role functioning domains. Xerostomia persisted during follow-up. Patients with high baseline immunohistochemical PSMA expression or DNA damage repair alterations tended to have longer OS.

Conclusions: TAT with Ac-PSMA resulted in remarkable survival and biochemical responses in advanced mCRPC patients. Patients experienced clinically relevant QoL improvement, although xerostomia was found to be nontransient. Baseline immunohistochemical PSMA expression and DNA damage repair status are potential predictive biomarkers of response to Ac-PSMA TAT.
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http://dx.doi.org/10.1016/j.urolonc.2020.12.002DOI Listing
December 2020

Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA.

Eur Urol 2021 Mar 5;79(3):343-350. Epub 2020 Dec 5.

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), partnersite Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer (mCRPC), but its antitumor effect can decrease over time.

Objective: To report the safety and activity of alpha-emitting Ac-225-PSMA-617 RLT in mCRPC that has progressed after Lu-177-PSMA.

Design, Setting, And Participants: Twenty-six patients were treated under a compassionate use protocol. The eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, progression after Lu-177-PSMA, and positive PSMA-ligand uptake. The median number of previous mCRPC regimens was 6. Ac-225-PSMA-617 was given every 8 wk until progression/intolerable side effects.

Outcome Measurements And Statistical Analysis: Prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and toxicity were measured.

Results And Limitations: Sixty-one cycles of Ac-225-PSMA-617 (median number of cycles 2; median activity 9 MBq) were administered. A PSA decline of ≥50% was achieved in 17/26 patients. The median PSA-PFS, cPFS, and OS periods were 3.5 (95% confidence interval [CI] 1.8-11.2), 4.1 (95% CI 3-14.8), and 7.7 (95% CI 4.5-12.1) mo, respectively. Liver metastases were associated with shorter PSA-PFS (median 1.9 vs 4.0 mo; p = 0.02), cPFS (median 1.8 vs 5.2 mo; p = 0.001), and OS (median 4.3 vs 10.4 mo; p = 0.01). Hematological grade 3/4 toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia (19%). All patients experienced grade 1/2 xerostomia. Two and six patients stopped due to hematological toxicity and xerostomia, respectively. A limitation is the retrospective design.

Conclusions: Ac-225-PSMA-617 showed measurable antitumor effect after Lu-177-PSMA failure in late-stage mCRPC. Grade 3/4 hematological side effects were observed in up to one-third of patients, and xerostomia led to treatment halt in a relevant number of patients.

Patient Summary: Ac-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy showed substantial antitumor effect in late metastatic castration-resistant prostate cancer after Lu-177-PSMA failure. However, dry mouth is a common side effect that caused about a quarter of patients to stop therapy.
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http://dx.doi.org/10.1016/j.eururo.2020.11.013DOI Listing
March 2021

Trastuzumab Modified Barium Ferrite Magnetic Nanoparticles Labeled with Radium-223: A New Potential Radiobioconjugate for Alpha Radioimmunotherapy.

Nanomaterials (Basel) 2020 Oct 20;10(10). Epub 2020 Oct 20.

Institute of Nuclear Chemistry and Technology, Dorodna 16 Str., 03-195 Warsaw, Poland.

Barium ferrite nanoparticles (BaFeNPs) were investigated as vehicles for Ra radionuclide in targeted α-therapy. BaFe nanoparticles were labeled using a hydrothermal Ba cations replacement by Ra with yield reaching 61.3 ± 1.8%. Radiolabeled nanoparticles were functionalized with 3-phosphonopropionic acid (CEPA) linker followed by covalent conjugation to trastuzumab (Herceptin). Thermogravimetric analysis and radiometric method with the use of [I]-labeled trastuzumab revealed that on average 19-21 molecules of trastuzumab are attached to the surface of one BaFe-CEPA nanoparticle. The hydrodynamic diameter of BaFe-CEPA-trastuzumab conjugate is 99.9 ± 3.0 nm in water and increases to 218.3 ± 3.7 nm in PBS buffer, and the zeta potential varies from +27.2 ± 0.7 mV in water to -8.8 ± 0.7 in PBS buffer. The [Ra]BaFe-CEPA-trastuzumab radiobioconjugate almost quantitatively retained Ra (>98%) and about 96% of Bi and 94% of Pb over 30 days. The obtained radiobioconjugate exhibited high affinity, cell internalization and cytotoxicity towards the human ovarian adenocarcinoma SKOV-3 cells overexpressing HER2 receptor. Confocal studies indicated that [Ra]BaFe-CEPA-trastuzumab was located in peri-nuclear space. High cytotoxicity of the [Ra]BaFe-CEPA-trastuzumab bioconjugate was confirmed by radiotoxicity studies on SKOV-3 cell monolayers and 3D-spheroids. In addition, the magnetic properties of the radiobioconjugate should allow for its use in guide drug delivery driven by magnetic field gradient.
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http://dx.doi.org/10.3390/nano10102067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589850PMC
October 2020

An octadentate bis(semicarbazone) macrocycle: a potential chelator for lead and bismuth radiopharmaceuticals.

Dalton Trans 2020 Nov;49(42):14962-14974

School of Biomedical Engineering and Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, UK.

A variant of 1,4,7,10-tetraazacyclododecane (cyclen) bearing two semicarbazone pendant groups has been prepared. The octadentate ligand forms complexes with Bi3+ and Pb2+. X-ray crystallography showed that the neutral ligand provides an eight-coordinate environment for both metal ions and intermolecular hydrogen bond interactions have influenced the coordination environments of both complexes in the solid state. NMR spectroscopy revealed a fluxional environment for both complexes. The ligand was radiolabeled with the α-emitting radioactive isotope 213Bi3+, which is used in systemic targeted radiotherapy. The resulting complex was stable in serum for at least 90 min (two decay half-lives). The Pb2+ complex has reasonably fast kinetics of formation (t1/2 = 20 min) at 25 °C and pH 7.4. The Bi3+ and Pb2+ complexes show kinetic stability in 1.2 M HCl (half-lives of 214 min and 47 min, respectively). This is the first description of a macrocycle bearing semicarbazone pendant groups and its utility in coordinating main group metals, specifically those with radiotherapeutic potential.
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http://dx.doi.org/10.1039/d0dt02673eDOI Listing
November 2020

Therapeutic Efficacy of Bi-labeled sdAbs in a Preclinical Model of Ovarian Cancer.

Mol Pharm 2020 09 13;17(9):3553-3566. Epub 2020 Aug 13.

In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium.

Targeted alpha-particle therapy (TAT) might be a relevant therapeutic strategy to circumvent resistance to conventional therapies in the case of HER2-positive metastatic cancer. Single-domain antibody fragments (sdAb) are promising vehicles for TAT because of their excellent properties, high target affinity, and fast clearance kinetics. This study combines the cytotoxic α-particle emitter bismuth-213 (Bi) and HER2-targeting sdAbs. The specificity, affinity, and cytotoxic potency of the radiolabeled complex were analyzed on HER2 cells. Its biodistribution through serial dissections and Cherenkov and micro-single-photon emission computed tomography (CT)/CT imaging was evaluated. Finally, the therapeutic efficacy and potential associated toxicity of [Bi]Bi-DTPA-2Rs15d were evaluated in a HER2 tumor model that manifests peritoneal metastasis. , [Bi]Bi-DTPA-2Rs15d bound HER2 cells in a HER2-specific way. In mice, high tumor uptake was reached already 15 min after injection, and extremely low uptake values were observed in normal tissues. Co-infusion of gelofusine resulted in a 2-fold reduction in kidney uptake. Administration of [Bi]Bi-DTPA-2Rs15d alone and in combination with trastuzumab resulted in a significant increase in median survival. We describe for the very first time the successful labeling of an HER2-sdAb with the α-emitter Bi, and after intravenous administration, revealing high stability and specific accumulation in target tissue and resulting in an increased median survival of these mice especially in combination with trastuzumab. These results indicate the potential of [Bi]Bi-DTPA-sdAb as a new radioconjugate for TAT, alone and as an add-on to trastuzumab for the treatment of HER2 metastatic cancer.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00580DOI Listing
September 2020

First-Generation Bispidine Chelators for Bi Radiopharmaceutical Applications.

ChemMedChem 2020 08 2;15(16):1591-1600. Epub 2020 Jul 2.

Universität Heidelberg, Anorganisch-Chemisches Institut, Neuenheimer Feld 270, 69120, Heidelberg, Germany.

Hepta- and octadentate bispidines (3,7-diazabicyclo[3.3.1]nonane, diaza-adamantane) with acetate, methyl-pyridine, and methyl-picolinate pendant groups at the amine donors of the bispidine platform have been prepared and used to investigate Bi coordination chemistry. Crystal structure and solution spectroscopic data (NMR spectroscopy and mass spectrometry) confirm that the rigid and relatively large bispidine cavity with an axially distorted geometry is well suited for Bi and in all cases forms nine-coordinate complexes; this is supported by an established hole size and shape analysis. It follows that nonadentate bispidines probably will be more suited as bifunctional chelators for Bi -based radiopharmaceuticals. However, two isomeric picolinate-/acetate-based heptadentate ligands already show very efficient complexation kinetics with Bi at ambient temperature and kinetic stability that is comparable with the standard ligands used in this field. The experimentally determined hydrophilicities (log D values) show that the Bi complexes reported are relatively hydrophilic and well suited for medicinal applications. We also present a very efficient and relatively accurate method to compute charge distributions and hydrophilicities, and this will help to further optimize the systems reported here.
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http://dx.doi.org/10.1002/cmdc.202000361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496608PMC
August 2020

First patient exceeding 5-year complete remission after Ac-PSMA-TAT.

Eur J Nucl Med Mol Imaging 2021 Jan 28;48(1):311-312. Epub 2020 May 28.

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

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http://dx.doi.org/10.1007/s00259-020-04875-yDOI Listing
January 2021

Preclinical Targeted α- and β-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies.

Cancers (Basel) 2020 Apr 21;12(4). Epub 2020 Apr 21.

In vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, Belgium.

HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic γ- and therapeutic α- and β-emitting radionuclides for the detection and treatment of HER2 brain lesions in a preclinical setting. 2Rs15d was radiolabeled with In, Ac and I using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for I- and Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2 tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2 SK-OV-3-Luc-IP1 and HER2 MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [I]-2Rs15d and [Ac]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2 metastatic cancer.
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http://dx.doi.org/10.3390/cancers12041017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226418PMC
April 2020

Ac- and Bi-Substance P Analogues for Glioma Therapy.

Semin Nucl Med 2020 Mar;50(2):141-151

Department of Neurosurgery, Bern and University of Basel, Switzerland.

Within the last decades, there has been no major improvement in treatment of patients with glioma, especially with glioblastoma multiforme (GBM) which is related to specific features of this tumor type, such as heterogeneity at the macroscopic, microscopic and genetic level, the infiltrative nature of tumors and the obstacle of the brain-blood barrier which limits the accessability of most drugs. The current standard of care is surgical resection, followed by radio- and chemotherapy. After first-line treatment of the primary lesion, tumor recurrence is diagnosed in virtually all GBM patients. Treatment of tumor recurrence represents a challenging clinical task. Surgical resection to relief symptoms of mass effect and/or salvage chemotherapy are often considered as last therapeutic option. A new treatment option is urgently needed. Targeted alpha therapy with an intratumoral injection of Bi-DOTA-Substance P (SP) or Ac-DOTAGA-Substance P has been introduced into the therapeutic armamentarium of recurrent GBM. There are many advantages of using SP such as very high prevalence of increased NK-1 expression in GBM cells, regardless of the degree of malignancy, and expression of the NK-1 receptor system not only on the membrane of cancer cells but also strong expression of NK1 receptors within the tumor neovasculature suggesting concomitant targeting of vascular and neoplastic structures. Radioisotopes with different physical properties, mainly beta-emitting metallic radionuclides, were implemented for brain tumor treatment. Based on their radiophysical properties, however, alpha emitters exhibit more promising properties. In investigator-initiated phase I and II studies, targeted alpha therapy using Bi-213/Ac-225 radiolabeled Substance P for malignant gliomas compare favorably with standard therapy, with the limitation that no large controlled series have so far been generated. Further development should focus on the improvement of the biological and chemical properties of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within growth and infiltrative zone of these glial neoplasms.
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http://dx.doi.org/10.1053/j.semnuclmed.2019.11.004DOI Listing
March 2020

Supply and Clinical Application of Actinium-225 and Bismuth-213.

Semin Nucl Med 2020 03 21;50(2):119-123. Epub 2020 Feb 21.

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

The recent development of Ac-PSMA617 for therapy of prostate cancer has strikingly demonstrated the clinical potential of targeted alpha therapy. Further promising applications of the alpha emitters Actinium and its daughter nuclide Bismuth include the therapy of brain tumors, bladder cancer, neuroendocrine tumors, and leukemia. This paper will provide a brief overview on the current status of the clinical development of compounds labelled with Ac or Bi and describe the various production routes that are in place or are under development to meet the increasing demand for these radionuclides.
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http://dx.doi.org/10.1053/j.semnuclmed.2020.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082773PMC
March 2020

Trastuzumab Conjugated Superparamagnetic Iron Oxide Nanoparticles Labeled with Ac as a Perspective Tool for Combined α-Radioimmunotherapy and Magnetic Hyperthermia of HER2-Positive Breast Cancer.

Molecules 2020 Feb 25;25(5). Epub 2020 Feb 25.

Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland.

It has been proven and confirmed in numerous repeated tests, that the use of a combination of several therapeutic methods gives much better treatment results than in the case of separate therapies. Particularly promising is the combination of ionizing radiation and magnetic hyperthermia in one drug. To achieve this objective, magnetite nanoparticles have been modified in their core with α emitter Ac, in an amount affecting only slightly their magnetic properties. By 3-phosphonopropionic acid (CEPA) linker nanoparticles were conjugated covalently with trastuzumab (Herceptin®), a monoclonal antibody that recognizes ovarian and breast cancer cells overexpressing the HER2 receptors. The synthesized bioconjugates were characterized by transmission electron microscopy (TEM), Dynamic Light Scattering (DLS) measurement, thermogravimetric analysis (TGA) and application of I-labeled trastuzumab for quantification of the bound biomolecule. The obtained results show that one Ac@FeO-CEPA-trastuzumab bioconjugate contains an average of 8-11 molecules of trastuzumab. The labeled nanoparticles almost quantitatively retain Ac (>98%) in phosphate-buffered saline (PBS) and physiological salt, and more than 90% of Fr and Bi over 10 days. In human serum after 10 days, the fraction of Ac released from Ac@FeO was still less than 2%, but the retention of Fr and Bi decreased to 70%. The synthesized Ac@FeO-CEPA-trastuzumab bioconjugates have shown a high cytotoxic effect toward SKOV-3 ovarian cancer cells expressing HER2 receptor in-vitro. The in-vivo studies indicate that this bioconjugate exhibits properties suitable for the treatment of cancer cells by intratumoral or post-resection injection. The intravenous injection of the Ac@FeO-CEPA-trastuzumab radiobioconjugate is excluded due to its high accumulation in the liver, lungs and spleen. Additionally, the high value of a specific absorption rate (SAR) allows its use in a new very perspective combination of α radionuclide therapy with magnetic hyperthermia.
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http://dx.doi.org/10.3390/molecules25051025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179151PMC
February 2020

Uptake and subcellular distribution of radiolabeled polymersomes for radiotherapy.

Nanotheranostics 2020 1;4(1):14-25. Epub 2020 Jan 1.

Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

Polymersomes have the potential to be applied in targeted alpha radionuclide therapy, while in addition preventing release of recoiling daughter isotopes. In this study, we investigated the cellular uptake, post uptake processing and intracellular localization of polymersomes. High-content microscopy was used to validate polymersome uptake kinetics. Confocal (live cell) microscopy was used to elucidate the uptake mechanism and DNA damage induction. Intracellular distribution of polymersomes in 3-D was determined using super-resolution microscopy. We found that altering polymersome size and concentration affects the initial uptake and overall uptake capacity; uptake efficiency and eventual plateau levels varied between cell lines; and mitotic cells show increased uptake. Intracellular polymersomes were transported along microtubules in a fast and dynamic manner. Endocytic uptake of polymersomes was evidenced through co-localization with endocytic pathway components. Finally, we show the intracellular distribution of polymersomes in 3-D and DNA damage inducing capabilities of Bi labeled polymersomes. Polymersome size and concentration affect the uptake efficiency, which also varies for different cell types. In addition, we present advanced assays to investigate uptake characteristics in detail, a necessity for optimization of nano-carriers. Moreover, by elucidating the uptake mechanism, as well as uptake extent and geometrical distribution of radiolabeled polymersomes we provide insight on how to improve polymersome design.
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http://dx.doi.org/10.7150/ntno.37080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940201PMC
January 2020

Prostate-specific membrane antigen-targeted endoradiotherapy in metastatic prostate cancer.

Curr Opin Urol 2020 01;30(1):98-105

Department of Nuclear Medicine, University of Pretoria, Pretoria, South Africa European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

Purpose Of Review: In this review, we present an update on the safety and efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PRLT) of metastatic castration-resistant prostate cancer (mCRPC).

Recent Findings: Treatment of mCRPC with approved treatment agents leads to a survival advantage. The disease often progresses despite these treatments. PRLT with Lutetium-177 and Actinium-225 labeled with PSMA (LuPSMA and AcPSMA) have recently been shown to be effective and well tolerated for mCRPC treatment. LuPSMA is currently applied in patients who have exhausted approved treatment options or in whom these approved treatments are contraindicated. In this category of heavily pretreated patients, prostate-specific antigen (PSA) response (≥50% decline) is achieved in about 46% of patients. Side-effects are tolerable with rare reports of grade III-IV treatment-induced toxicity. AcPSMA is currently applied on a smaller scale in patients who relapsed after LuPSMA or in whom LuPSMA is contraindicated. PSA response occurs in up to 88% of patients treated with AcPSMA.

Summary: PRLT with LuPSMA and AcPSMA is a well-tolerated and effective treatment modality for mCRPC. Prospective randomized control trials are necessary to facilitate its application as an approved therapy option.
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http://dx.doi.org/10.1097/MOU.0000000000000685DOI Listing
January 2020

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair-Associated Genes.

J Nucl Med 2020 05 10;61(5):683-688. Epub 2019 Oct 10.

Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Prostate-specific membrane antigen (PSMA)-targeting α-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT-nonresponding lesions by targeted next-generation sequencing. Of 60 patients treated with Ac-PSMA-617, we identified 10 patients who presented with a poor response despite sufficient tumor uptake in PSMA PET/CT. We were able to perform CT-guided biopsies with histologic validation of the nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair-associated genes. In the 7 tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting ( = 3), ( = 2), ( = 2), and and ( = 1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in and various genes were detected. Patients with resistance to PSMA-TAT despite PSMA positivity frequently harbor mutations in DNA damage-repair and checkpoint genes. Although the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA damage-repair-targeting agents such as poly(ADP-ribose)-polymerase inhibitors.
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http://dx.doi.org/10.2967/jnumed.119.234559DOI Listing
May 2020

Development of Targeted Alpha Therapy from Bench to Bedside.

J Med Imaging Radiat Sci 2019 Dec 9;50(4S1):S18-S20. Epub 2019 Aug 9.

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

This review briefly describes recent promising developments of alpha emitter labelled compounds for targeted alpha therapy of bladder cancer, brain tumours, neuroendocrine tumours, and prostate cancer.
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http://dx.doi.org/10.1016/j.jmir.2019.06.046DOI Listing
December 2019

Targeted alpha therapy with bismuth-213 and actinium-225: Meeting future demand.

J Labelled Comp Radiopharm 2019 Sep 1;62(11):794-802. Epub 2019 Aug 1.

European Commission, Joint Research Centre (JRC), Karlsruhe, Germany.

Targeted alpha therapy (TAT) is a promising approach for the treatment of cancer. The use of alpha emitters for cancer therapy has two distinct advantages over conventional therapies. The short range of alpha radiation in human tissue (less than 0.1 mm), corresponding to only a few cell diameters, allows selective killing of targeted cancer cells while sparing surrounding healthy tissue. At the same time, the high energy (several MeV) of alpha radiation and its associated high linear energy transfer leads to highly effective cell kill. Consequently, alpha radiation can destroy cells which otherwise exhibit resistance to treatment with beta or gamma irradiation or chemotherapeutic drugs, and can thus offer a therapeutic option for tumors resistant to conventional therapies. Recent results demonstrating the remarkable therapeutic efficacy of alpha emitters to treat various cancers have underlined the clinical potential of TAT. This paper describes the recent clinical experience with Bi and Ac. In view of the enormous benefit of targeted cancer treatment with alpha emitters, their production will have to be considerably increased beyond current supply capabilities. Alternative production methods based on the irradiation of uranium, thorium, or radium targets at reactors or accelerator facilities have the potential to meet future demand.
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http://dx.doi.org/10.1002/jlcr.3792DOI Listing
September 2019

Correction to: Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study.

Eur J Nucl Med Mol Imaging 2019 Sep;46(10):1988

Department of Nuclear Medicine, Steve Biko Academic Hospital, University of Pretoria, Private Bag X169, Pretoria, 0001, South Africa.

The author of this article wanted to change the ethical approval statement of the originally published version of this article. Correct statement is indicated below.
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http://dx.doi.org/10.1007/s00259-019-04401-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828288PMC
September 2019

Assessment of Bi-anti-EGFR MAb treatment efficacy in malignant cancer cells with [1-C]pyruvate and [F]FDG.

Sci Rep 2019 06 5;9(1):8294. Epub 2019 Jun 5.

Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich, Germany.

Evaluation of response to therapy is among the key objectives of oncology. A new method to evaluate this response includes magnetic resonance spectroscopy (MRS) with hyperpolarized C-labelled metabolites, which holds promise to provide new insights in terms of both therapeutic efficacy and tumor cell metabolism. Human EJ28Luc urothelial carcinoma and LN18 glioma cells were treated with lethal activity concentrations of a Bi-anti-EGFR immunoconjugate. Treatment efficacy was controlled via analysis of DNA double-strand breaks (immunofluorescence γH2AX staining) and clonogenic survival of cells. To investigate changes in metabolism of treated cells vs controls we analyzed conversion of hyperpolarized [1-C]pyruvate to [1-C]lactate via MRS as well as viability of cells, lactate formation and lactate dehydrogenase activity in the cellular supernatants and [F]FDG uptake in treated cells vs controls, respectively. Treatment of malignant cancer cells with Bi-anti-EGFR-MAb induced intense DNA double-strand breaks, resulting in cell death as monitored via clonogenic survival. Moreover, treatment of EJ28Luc bladder cancer cells resulted in decreased cell viability, [F]FDG-uptake and an increased lactate export. In both EJ28Luc and LN18 carcinoma cells treatment with Bi-anti-EGFR-MAb triggered a significant increase in lactate/pyruvate ratios, as measured with hyperpolarized [1-C]pyruvate. Treatment with Bi-anti-EGFR-MAb resulted in an effective induction of cell death in EJ28Luc and LN18 cells. Lactate/pyruvate ratios of hyperpolarized [1-C]pyruvate proved to detect early treatment response effects, holding promise for future clinical applications in early therapy monitoring.
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http://dx.doi.org/10.1038/s41598-019-44484-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549183PMC
June 2019

Treatment of brain metastases of castration-resistant prostate cancer with Ac-PSMA-617.

Eur J Nucl Med Mol Imaging 2019 Jul 21;46(8):1756-1757. Epub 2019 May 21.

Department of Nuclear Medicine, University of Pretoria, Private Bag X169, Pretoria, 0001, South Africa.

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http://dx.doi.org/10.1007/s00259-019-04354-zDOI Listing
July 2019

DNA damage in human whole blood caused by radiopharmaceuticals evaluated by the comet assay.

Mutagenesis 2019 09;34(3):239-244

Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld, Heidelberg, Germany.

Radiopharmaceuticals used for diagnosis or therapy induce DNA strand breaks, which may be detectable by single-cell gel electrophoresis (called comet assay). Blood was taken from patients before and at different time points after treatment with radiopharmaceuticals; blood cells were investigated by the comet assay using the percentage of DNA in the tail as the critical parameter. Whereas [225Ac]Ac-prostate-specific membrane antigen (PSMA)-617 alpha therapy showed no difference relative to the blood sample taken before treatment, beta therapy with [177Lu]Lu-PSMA-617 3 h post-injection revealed a small but significant increase in DNA strand breaks. In blood of patients who underwent positron emission tomography (PET) with either [18F]2-fluor-2-deoxy-D-glucose (FDG) or [68Ga]Ga-PSMA-11, an increase of DNA migration determined by the comet assay was not found when analysed at different time points (2-70 min) after intravenous tracer injection. Human whole blood was incubated with the targeted clinically relevant therapeutic radiopharmaceuticals [225Ac]Ac-PSMA-617, [177Lu]Lu-PSMA-617 and [90Y]Y-DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTA-TOC) at different activity concentrations (kBq/ml) for 5 days and then analysed by the comet assay. DNA damage increased with higher concentrations of all radiolabeled compounds tested. [177Lu]Lu-PSMA-617 caused higher blood cell radiotoxicity than equal activity concentrations of [90Y]Y-DOTA-TOC. Likewise, whole human blood was exposed to the positron emitters [18F]FDG and [68Ga]Ga-PSMA-11 in vitro for 24 h with activity concentrations ranging between 5 and 40 MBq/ml. The same activity concentration dependent elevated DNA migration was observed for both compounds although decay energies are different. This study demonstrated that the amount of DNA damage detected by the comet assay in whole human blood is similar among different positron emitters and divergent by a factor of 200 between alpha particles and beta radiation.
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http://dx.doi.org/10.1093/mutage/gez007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753384PMC
September 2019

Predictors of Overall and Disease-Free Survival in Metastatic Castration-Resistant Prostate Cancer Patients Receiving Ac-PSMA-617 Radioligand Therapy.

J Nucl Med 2020 01 17;61(1):62-69. Epub 2019 May 17.

Department of Nuclear Medicine, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa.

Metastatic prostate carcinoma overexpresses prostate-specific membrane antigen (PSMA), making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience with a series of 73 castration-resistant prostate carcinoma patients treated with Ac-PSMA-617, identifying variables predictive for overall survival (OS) and progression-free survival (PFS) after Ac-PSMA-617 treatment. Ac-PSMA-617 was administered to patients who had metastatic castration-resistant prostate carcinoma and who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate, and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up for selection of patients for treatment, to determine the activity of the treatment agent to be administered, and for response assessment. Serial prostate-specific antigen (PSA) was obtained for PSA response assessment. Seventy-three men (mean age, 69 y; range, 45-85 y) with metastatic castration-resistant prostate carcinoma were treated with 210 cycles of Ac-PSMA-617. In 70% of patients, a PSA decline of greater than or equal to 50% was obtained; 82% of patients had any PSA decline. In 29% of patients, all lesions on Ga-PSMA PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression, whereas 13 patients died from their disease. The estimated median PFS and OS were 15.2 mo (95% CI, 13.1-17.4) and 18 mo (95% CI, 16.2-19.9), respectively. In univariate analyses, factors such as baseline PSA, any PSA decline, PSA decline of greater than or equal to 50%, prior chemotherapy, prior radiation therapy, and baseline hemoglobin level were associated with longer PFS and OS (all s < 0.05). In multivariate analyses, there was a negative association between prior Lu-PSMA therapy and PFS, and a positive association between PSA decline of greater or equal to 50% and PFS. Only a PSA decline of greater than or equal to 50% remained significantly associated with OS on multivariate analyses. Xerostomia was seen in 85% of patients but was not severe enough to warrant discontinuing treatment. Anemia was seen in 27 patients; no patients had grade IV bone marrow toxicity. Renal failure of grade III or IV was seen in 5 patients with baseline renal impairment. In this study, a PSA decline of greater than or equal to 50% after treatment with Ac-PSMA-617 was proven by multivariate analyses to be significantly associated with OS and PFS. Furthermore, previous Lu-PSMA treatment was negatively associated with PFS in both univariate and multivariate analyses.
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http://dx.doi.org/10.2967/jnumed.119.229229DOI Listing
January 2020

Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy.

Clin Cancer Res 2019 08 6;25(15):4775-4790. Epub 2019 May 6.

IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France.

Purpose: For the development of new anticancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of nontargeted effects in nonirradiated neighboring cells, because they may affect the therapeutic efficacy and contribute to side effects.

Experimental Design: Here, we investigated the contribution of nontargeted cytotoxic and genotoxic effects and (in xenografted mice) during alpha (Pb/Bi, Bi) and Auger (I) radioimmunotherapy (RIT).

Results: Between 67% and 94% (alpha RIT) and 8% and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7% to 36% (alpha RIT) and 27% to 29% (Auger RIT) of cells were killed by nontargeted effects. We then demonstrated that the nontargeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and JNK. Reactive oxygen species also played a significant role in these nontargeted effects, as demonstrated by NF-κB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival and to larger tumors and less tissue DNA damage . These results were supported by an inhibitory effect of pravastatin on Auger RIT.

Conclusions: Cell membrane-mediated nontargeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3295DOI Listing
August 2019

Safety and efficacy of targeted alpha therapy with Bi-DOTA-substance P in recurrent glioblastoma.

Eur J Nucl Med Mol Imaging 2019 03 29;46(3):614-622. Epub 2018 Nov 29.

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

Treatment options for recurrent glioblastoma multiforme (GBM) are very limited. GBM cells express high levels of the GPCR neurokinin type 1 receptor (NK-1R), and a modified substance P can be used as its ligand for the tumor cell targeting. Targeted alpha therapy with DOTA-Substance P labeled with the short range alpha emitter Bi allows for selective irradiation and killing of tumor cells.

Material And Methods: Twenty patients with recurrent GBM were included into the study following a standard therapy. 1-2 intracavitary or intratumoral port-a-cath systems were stereotactically inserted. Patients were treated with 1-7 doses of Bi-DOTA-Substance P (Bi-DOTA-SP) in 2-month intervals. Ga-DOTA-Substance P (Ga-DOTA-SP) was co-injected with Bi-DOTA-SP to assess the biodistribution using PET/CT. Therapeutic response was monitored with performance status and MRI imaging.

Results: Treatment with activity up to 11.2 GBq Bi-DOTA-SP was well tolerated with only mild and transient adverse reactions. The median progression free survival was 2.7 months. The median overall survival from the first diagnosis was 23.6 months and median survival after recurrence was 10.9 months. The median survival time from the start of Bi-DOTA-SP was 7.5 months.

Conclusions: Treatment of recurrent GBM with Bi-DOTA-SP is safe and well tolerated. The median overall survival after recurrence of 10.9 months compares favorably to the available alternative treatment options. Once the supply of high activity Ac/Bi radionuclide generators is secured, targeted alpha therapy with Bi-DOTA-SP may evolve as a promising novel option to treat recurrent GBM.
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http://dx.doi.org/10.1007/s00259-018-4225-7DOI Listing
March 2019

Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study.

Eur J Nucl Med Mol Imaging 2019 01 19;46(1):129-138. Epub 2018 Sep 19.

Department of Nuclear Medicine, Steve Biko Academic Hospital, University of Pretoria, Private Bag X169, Pretoria, 0001, South Africa.

Background: A remarkable therapeutic efficacy has been demonstrated with Ac-prostate-specific membrane antigen (PSMA)-617 in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients. We report our experience with Ac-PSMA-617 therapy in chemotherapy-naïve patients with advanced metastatic prostate carcinoma.

Methods: Seventeen patients with advanced prostate cancer were selected for treatment with Ac-PSMA-617 in 2-month intervals, with initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In one patient, activity was escalated to 13 MBq in the third cycle. Fourteen patients had three treatment cycles administered, while in three patients treatment was discontinued after two cycles due to good response. Six out of 17 patients received additional treatments after the third cycle. Prostate-specific antigen (PSA) was measured every 4 weeks for PSA response assessment. Ga-PSMA-PET/CT was used for functional response assessment before each subsequent treatment cycle. Serial full blood count, renal function test, and liver function were obtained to determine treatment-related side effects.

Results: Good antitumor activity assessed by serum PSA level and Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, PSA decline ≥90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of Ac-PSMA-617. Fifteen of 17 patients had a > 50% decline in lesions avidity for tracer on Ga-PSMA-PET/CT including 11 patients with complete resolution (PET-negative and either stable sclerosis on CT for bone or resolution of lymph node metastases) of all metastatic lesions. Grade 1/2 xerostomia was seen in all patients, and none was severe enough to lead to discontinuation of treatment. One patient had with extensive bone marrow metastases and a background anemia developed a grade 3 anemia while another patient with solitary kidney and pre-treatment grade 3 renal failure developed grade 4 renal toxicity following treatment. The group presented with significant palliation of bone pain and reduced toxicity to salivary glands due to de-escalation.

Conclusions: Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.
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http://dx.doi.org/10.1007/s00259-018-4167-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267694PMC
January 2019

Initial clinical experience performing sialendoscopy for salivary gland protection in patients undergoing Ac-PSMA-617 RLT.

Eur J Nucl Med Mol Imaging 2019 01 27;46(1):139-147. Epub 2018 Aug 27.

Department of Otorhinolaryngology, Head and Neck Surgery (ORL-HNS), Heidelberg University Hospital, Heidelberg, Germany.

Purpose: The main side effect of prostate-specific membrane antigen targeting alpha therapy (PSMA TAT) is dry mouth syndrome. Inflammation of the salivary glands and consequent reduced salivary function have been reported in patients after radioiodine therapy. The beneficial effects of sialendoscopy on radiation-induced inflammation in tissue are well known. Thus sialendoscopy with dilatation, saline irrigation and steroid injections (prednisolone) was performed before and after Ac-PSMA-617 TAT to reduce inflammatory effects in the salivary glands and to improve or prevent xerostomia.

Methods: Eleven men with metastatic castration-resistant prostate cancer (mean age 68.5 years, range 58-80 years) underwent sialendoscopy, dilatation, saline irrigation and steroid injection of both submandibular and both parotid glands before or after every cycle of Ac-PSMA-617 TAT. Sialendoscopy and steroid injection were performed by a senior ENT physician. Quality of life was evaluated using two health-related quality of life (HRQOL) questionnaires, the Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI) before and 3 months after the intervention.

Results: In all 11 patients both parotid and both submandibular glands were affected by radiation sialadenitis and sialendoscopy was performed. The patients experienced no complications after sialendoscopy, and showed a significant improvement in HRQOL as measured using the XQ and XI. After sialendoscopy the XQ score decreased significantly from 77.7 ± 13.6 to 42.7 ± 14.8 (p = 0.003) and the XI score decreased from 44.5 ± 6.9 to 25.8 ± 12.8 (p = 0.003). Due to the limited number of patients we only report tendencies.

Conclusion: Sialendoscopy with dilatation, saline irrigation and steroid injection had beneficial effects on salivary gland function and HRQOL in patients undergoing Ac-PSMA-617 RLT. However, even with sialadenoscopic support after multiple cycles of TAT, salivary gland function was reduced and xerostomia was present. Therefore, not only inflammation but also the direct effect of radiation is a putative cause of dry mouth. Further research is necessary to determine the main side effects of PSMA TAT.
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http://dx.doi.org/10.1007/s00259-018-4135-8DOI Listing
January 2019

Efficient formation of inert Bi-213 chelates by tetraphosphorus acid analogues of DOTA: towards improved alpha-therapeutics.

EJNMMI Res 2018 Aug 8;8(1):78. Epub 2018 Aug 8.

Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München,, Walther-Meißner-Strasse 3, 85748, Garching, Germany.

Background: The recently growing interest in targeted alpha-therapy (TAT) calls for improvement of the labelling chemistry of the corresponding radionuclides. Bi is a short-lived alpha emitter which emits only one alpha particle in its decay chain. Hence, it might be safer in application than other respective nuclides, such as Ra or Ac, because no alpha-emitting daughters are released upon recoil. We investigated cyclen derivatives with phosphorus-containing pendant arms regarding their suitability for Bi labelling.

Results: The concentration dependency of Bi labelling at 25 °C and 95 °C was determined for DOTP, DOTP, DOTP, and DOTPI, as well as for DOTA and CHX-A"-DTPA for comparison. The labelling efficiency of the phosphorus-containing ligands was at least comparable to CHX-A"-DTPA and exceeded that of DOTA. DOTP was most efficient, requiring chelator concentrations for labelling which were approx. two orders of magnitude lower than those required for CHX-A"-DTPA, both at 25 °C and 95 °C. The Bi complexes of phosphorus ligands furthermore showed a higher stability against demetallation (> 96% of intact complex after 120-min incubation in plasma were found for DOTP, DOTP, and DOTP, compared to 85% for DOTA and 76% for CHX-A"-DTPA).

Conclusion: Cyclen derivatives bearing four N-methylenephosphonic or -phosphinic acid substituents, e.g., DOTP, are capable of complexing the alpha-emitting radionuclide Bi with higher efficiency and in-vitro stability than the current gold standards DOTA and CHX-A"-DTPA.
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http://dx.doi.org/10.1186/s13550-018-0431-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082748PMC
August 2018

An Overview of Targeted Alpha Therapy with Actinium and Bismuth.

Curr Radiopharm 2018 ;11(3):200-208

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

Background: Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy.

Objective And Conclusion: This review describes methods for the production of 225Ac and its daughter nuclide 213Bi and summarizes the current clinical experience with both alpha emitters with particular focus on recent studies of targeted alpha therapy of bladder cancer, brain tumors, neuroendocrine tumors and prostate cancer.
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http://dx.doi.org/10.2174/1874471011666180502104524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237921PMC
January 2019

Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with Bi-substance P analogue.

Eur J Nucl Med Mol Imaging 2018 07 30;45(9):1636-1644. Epub 2018 Apr 30.

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

Background: Glioblastoma multiforme (GBM), the most common malignant brain tumor, mainly manifests as a primary de novo and less frequently as a secondary glial neoplasm. GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures.

Material And Methods: Among 50 glioma patients of different subtypes that have to date been treated with targeted alpha therapy at the Medical University Warsaw, we report here the data on nine patients with secondary GBM. Following surgery, chemo- and radiotherapy, recurrent GBM was treated by intracavitary injection of 1-6 doses of 0.9-2.3 GBq Bi- DOTA-[Thi,Met(O)]-substance P (Bi-DOTA-SP) in 2-month intervals. Ga-DOTA-[Thi,Met(O)]-substance P (Ga-DOTA-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI.

Results: Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy.

Conclusions: Targeted alpha therapy of secondary GBM with Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM.
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http://dx.doi.org/10.1007/s00259-018-4015-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061489PMC
July 2018

Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer.

J Nucl Med 2018 08 19;59(8):1234-1242. Epub 2018 Apr 19.

Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France

We have developed the 16F12 mouse monoclonal antibody (mAb), which targets the Müllerian-inhibiting substance receptor, type II (MISRII), expressed by ovarian tumors. Here, we assessed in preclinical models the possibility of using radiolabeled 16F12 in a theranostic approach for small-volume ovarian peritoneal carcinomatosis, such as after cytoreductive surgery. DOTA-, DTPA- or deferoxamine mesylate-conjugated 16F12 mAb was radiolabeled with β-particle (Lu) or α-particle (Bi) emitters for therapeutic use and with Zr for PET imaging. On the 13th postxenograft day, mice bearing intraperitoneal MISRII-positive AN3CA endometrial carcinoma cell xenografts were treated by conventional intraperitoneal radioimmunotherapy (IP-RIT) with 10 MBq of Lu-16F12 or 12.9 MBq of Bi-16F12 or by brief intraperitoneal radioimmunotherapy (BIP-RIT) using 50 MBq of Lu-16F12 or 37 MBq of Bi-16F12. For BIP-RIT, 30 min after injection of the radiolabeled mAbs, the peritoneal cavity was washed to remove the unbound radioactivity. The biodistribution of Lu- and Bi-16F12 mAbs was determined and then used for dose assessment. Hematologic toxicity was also monitored. The 16F12 mAb was satisfactorily radiolabeled for both therapy and imaging. IP-RIT with Lu-16F12 was slightly more efficient in delaying tumor growth than IP-RIT with Bi-16F12. Conversely, Bi-16F12 was more efficient than Lu-16F12 in BIP-RIT. The biodistribution analysis showed that the tumor-to-blood uptake ratio was significantly higher with BIP-RIT than with IP-RIT for both Bi- and Lu-16F12. Hematologic toxicity was more pronounced with Lu-16F12 than with Bi-16F12. SPECT/CT images (after BIP-RIT with Lu-16F12) and PET/CT images (after injection of Zr-16F12 in the tail vein) showed focal uptake at the tumor site. Radiolabeled 16F12 could represent a new theranostic tool for small-volume ovarian peritoneal carcinomatosis. Specifically, Bi-16F12-based BIP-RIT could be proposed to selected patients as an alternative adjuvant treatment immediately after cytoreductive surgery. An anti-MISRII mAb is currently being used in a first-in-human study, thus making radiolabeled anti-MISRII mAbs a realistic theranostic option for the clinic.
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http://dx.doi.org/10.2967/jnumed.118.208611DOI Listing
August 2018