Publications by authors named "Hans-Jürgen Pietzsch"

60 Publications

In reply to the Letter to the Editor by Chen and Lui regarding "Radiotherapy enhances uptake and efficacy of Y-cetuximab: A preclinical trial" by A Dietrich et al.

Radiother Oncol 2021 Jun 10. Epub 2021 Jun 10.

German Cancer Consortium (DKTK), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Helmholtz-Zentrum Dresden - Rossendorf, TU, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany.

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http://dx.doi.org/10.1016/j.radonc.2021.06.014DOI Listing
June 2021

Radiolabelled Cyclic Bisarylmercury: High Chemical and in vivo Stability for Theranostics.

ChemMedChem 2021 May 5. Epub 2021 May 5.

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328, Dresden, Germany.

We show the synthesis of an in vivo stable mercury compound with functionality suitable for radiopharmaceuticals. The designed cyclic bisarylmercury was based on the water tolerance of organomercurials, higher bond dissociation energy of Hg-Ph to Hg-S, and the experimental evidence that acyclic structures suffer significant cleavage of one of the Hg-R bonds. The bispidine motif was chosen for its in vivo stability, chemical accessibility, and functionalization properties. Radionuclide production results in HgCl (aq), so the desired mercury compound was formed via a water-tolerant organotin transmetallation. The Hg-bispidine compound showed high chemical stability in tests with an excess of sulfur-containing competitors and high in vivo stability, without any observable protein interaction by human serum assay, and good organ clearance demonstrated by biodistribution and SPECT studies in rats. In particular, no retention in the kidneys was observed, typical of unstable mercury compounds. The Hg analogue allowed full characterization by NMR and HRMS.
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http://dx.doi.org/10.1002/cmdc.202100131DOI Listing
May 2021

Towards Targeted Alpha Therapy with Actinium-225: Chelators for Mild Condition Radiolabeling and Targeting PSMA-A Proof of Concept Study.

Cancers (Basel) 2021 Apr 20;13(8). Epub 2021 Apr 20.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, Germany.

Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter Ac has excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis of two universal Ac-chelators for mild condition radiolabeling and binding to conjugate molecules of pharmacological interest via the copper-mediated click chemistry. A convenient radiolabeling procedure was investigated as well as the complex stability proved for both chelators and two PSMA (prostate-specific membrane antigen)-targeting model radioconjugates. Studies regarding affinity and cell survival were performed on LNCaP cells followed by biodistribution studies, which were performed using LNCaP tumor-bearing mice. High efficiency radiolabeling for all conjugates was demonstrated. Cell binding studies revealed a fourfold lower cell affinity for the PSMA radioconjugate with one targeting motif compared to the radioconjugate owing two targeting motifs. Additionally, these differences were verified by in vitro cell survival evaluation and biodistribution studies, both showing a higher cell killing efficiency for the same dose, a higher tumor uptake (15%ID/g) and a rapid whole body clearance after 24 h. The synthesized chelators will overcome obstacles of lacking stability and worse labeling needs regarding Ac complexation using the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) chelator. Moreover, the universal functionalization expands the coverage of these chelators in combination with any sensitive bio(macro)molecule, thus improving treatment of any addressable tumor target.
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http://dx.doi.org/10.3390/cancers13081974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073976PMC
April 2021

Radiotherapy enhances uptake and efficacy of Y-cetuximab: A preclinical trial.

Radiother Oncol 2021 02 21;155:285-292. Epub 2020 Nov 21.

German Cancer Consortium (DKTK), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany, Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Background And Purpose: Systemic molecular radiotherapy utilizes internal irradiation by radionuclide-labeled tumor-targeting agents with the potential to destroy (micro-)metastases. However, doses that are applicable in solid tumors do not reach the levels nessecary for tumor control. Thus, the combination of molecular and external radiotherapy is a promising treatment strategy, as enhanced tumor doses can be delivered with and without minor overlapping toxicities. Here, we combined a Y-labeled anti-EGFR antibody (Cetuximab) with clinically relevant fractionated radiotherapy in a preclinical trial using head and neck squamous cell carcinoma xenograft tumors.

Materials And Methods: To model Y-Cetuximab uptake for treatment schedule optimization, FaDu-bearing mice were injected with near-infrared-labeled-Cetuximab at different time points during radiotherapy with differing doses. Cetuximab uptake was longitudinally followed by in vivo-optical imaging. Tumor control probability experiments with fractionated radiotherapy (30 fx, 6 weeks, 8 dose groups/ arm) in combination with Y-Cetuximab were performed to test the curative potential.

Results: Imaging of near-infrared-labeled-Cetuximab uptake revealed that low to moderate external beam doses can enhance antibody uptake. Using the optimized schedule, combination of molecular and external radiotherapy using Y-Cetuximab at a dose that did not result in permanent tumor inactivation in previous experiments, led to substantially increased tumor control compared to radiotherapy alone.

Conclusion: Our results indicate that combination of radiolabeled therapeutics with clinically relevant fractionated radiotherapy has a remarkable potential to improve curative treatment outcome. Application of some radiation dose prior to injection may improve drug uptake and enable patient stratification and treatment personalization via a corresponding PET-tracer during therapy.
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http://dx.doi.org/10.1016/j.radonc.2020.11.013DOI Listing
February 2021

Recent Insights in Barium-131 as a Diagnostic Match for Radium-223: Cyclotron Production, Separation, Radiolabeling, and Imaging.

Pharmaceuticals (Basel) 2020 Sep 25;13(10). Epub 2020 Sep 25.

Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany.

Barium-131 is a single photon emission computed tomography (SPECT)-compatible radionuclide for nuclear medicine and a promising diagnostic match for radium-223/-224. Herein, we report on the sufficient production route Cs(,)Ba by using 27.5 MeV proton beams. An average of 190 MBq barium-131 per irradiation was obtained. The SR Resin-based purification process led to barium-131 in high radiochemical purity. An isotopic impurity of 0.01% barium-133 was detectable. For the first time, radiolabeling of the ligand macropa with barium-131 was performed. Radiolabeling methods under mild conditions and reaction controls based on TLC systems were successfully applied. Small animal SPECT/ computed tomography (CT) measurements and biodistribution studies were performed using [Ba]Ba(NO) as reference and Ba-labeled macropa in healthy mice for the first time. Biodistribution studies revealed the expected rapid bone uptake of [Ba]Ba, whereas Ba-labeled macropa showed a fast clearance from the blood, thereby showing a significantly ( < 0.001) lower accumulation in the bone. We conclude that barium-131 is a promising SPECT radionuclide and delivers appropriate imaging qualities in small animals. Furthermore, the relative stability of the Ba-labeled macropa complex in vivo forms the basis for the development of sufficient new chelators, especially for radium isotopes. Thereby, barium-131 will attain its goal as a diagnostic match to the alpha emitters radium-223 and radium-224.
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http://dx.doi.org/10.3390/ph13100272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599757PMC
September 2020

Sub-10 nm Radiolabeled Barium Sulfate Nanoparticles as Carriers for Theranostic Applications and Targeted Alpha Therapy.

ChemistryOpen 2020 08 8;9(8):797-805. Epub 2020 Jun 8.

Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden-Rossendorf Bautzner Landstraße 400 01328 Dresden Germany.

The treatment of cancer patients with α-particle-emitting therapeutics continues to gain in importance and relevance. The range of radiopharmaceutically relevant α-emitters is limited to a few radionuclides, as stable chelators or carrier systems for safe transport of the radioactive cargo are often lacking. Encapsulation of α-emitters into solid inorganic systems can help to diversify the portfolio of candidate radionuclides, provided, that these nanomaterials effectively retain both the parent and the recoil daughters. We therefore focus on designing stable and defined nanocarrier-based systems for various clinically relevant radionuclides, including the promising α-emitting radionuclide Ra. Hence, sub-10 nm barium sulfate nanocontainers were prepared and different radiometals like Zr, In, Ba, Lu or Ra were incorporated. Our system shows stabilities of >90 % regarding the radiometal release from the BaSO matrix. Furthermore, we confirm the presence of surface-exposed amine functionalities as well as the formation of a biomolecular corona.
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http://dx.doi.org/10.1002/open.202000126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397357PMC
August 2020

Sub-10 nm Radiolabeled Barium Sulfate Nanoparticles as Carriers for Theranostic Applications and Targeted Alpha Therapy.

ChemistryOpen 2020 08 3;9(8):796. Epub 2020 Aug 3.

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Bautzner Landstraße 400 01328 Dresden Germany.

10.1002/open.202000126.
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http://dx.doi.org/10.1002/open.202000201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397348PMC
August 2020

Single Photon Emission Computed Tomography Tracer.

Recent Results Cancer Res 2020 ;216:227-282

Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen-PSI, Zürich, Switzerland.

Single photon emission computed tomography (SPECT) is the state-of-the-art imaging modality in nuclear medicine despite the fact that only a few new SPECT tracers have become available in the past 20 years. Critical for the future success of SPECT is the design of new and specific tracers for the detection, localization, and staging of a disease and for monitoring therapy. The utility of SPECT imaging to address oncologic questions is dependent on radiotracers that ideally exhibit excellent tissue penetration, high affinity to the tumor-associated target structure, specific uptake and retention in the malignant lesions, and rapid clearance from non-targeted tissues and organs. In general, a target-specific SPECT radiopharmaceutical can be divided into two main parts: a targeting biomolecule (e.g., peptide, antibody fragment) and a γ-radiation-emitting radionuclide (e.g., Tc, I). If radiometals are used as the radiation source, a bifunctional chelator is needed to link the radioisotope to the targeting entity. In a rational SPECT tracer design, these single components have to be critically evaluated in order to achieve a balance among the demands for adequate target binding, and a rapid clearance of the radiotracer. The focus of this chapter is to depict recent developments of tumor-targeted SPECT radiotracers for imaging of cancer diseases. Possibilities for optimization of tracer design and potential causes for design failure are discussed and highlighted with selected examples.
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http://dx.doi.org/10.1007/978-3-030-42618-7_7DOI Listing
September 2020

A Ra-labeled polyoxopalladate as a putative radiopharmaceutical.

Chem Commun (Camb) 2019 Jun;55(53):7631-7634

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.

Despite their attractive properties, internal targeted alpha therapies using 223/224Ra are limited to bone-seeking applications. As there is no suitable chelator available, the search for new carriers to stably bind Ra2+ and to connect it to biological target molecules is necessary. Polyoxopalladates represent a class of compounds where Ra2+ can be easily introduced into the Pd-POM core during a facile one-pot preparation. Due to the formation of a protein corona, the connection to other targeting (bio)macromolecules is possible.
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http://dx.doi.org/10.1039/c9cc02587aDOI Listing
June 2019

Radiochemical and radiopharmacological characterization of a Cu-labeled α-MSH analog conjugated with different chelators.

J Labelled Comp Radiopharm 2019 06 17;62(8):495-509. Epub 2019 Jun 17.

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.

Radiolabeled α-melanocyte-stimulating hormone (α-MSH) derivatives have a high potential for diagnosis and treatment of melanoma, because of high specificity and binding affinity to the melanocortin-1 receptor (MC1R). Hence, the α-MSH-derived peptide NAP-NS1 with a β-Ala linker (ε-Ahx-β-Ala-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH ) was conjugated to different chelators: either to NOTA (p-SCN-Bn-1,4,7-triazacyclononane-1,4,7-triacetic acid), to a hexadentate bispidine carbonate derivative (dimethyl-9-(((4-nitrophenoxy)carbonyl)oxy)-2,4-di(pyridin-2-yl)-3,7-bis(pyridin-2-ylmethyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate), or to DMPTACN (p-SCN-Ph-bis(2-pyridyl-methyl)-1,4,7-triaza-cyclononane), labeled with Cu, and investigated in terms of radiochemical and radiopharmacological properties. For the three Cu-labeled conjugates negligible transchelation, suitable buffer and serum stability, as well as appropriate water solubility, was determined. The three conjugates exhibited high binding affinity (low nanomolar range) in murine B16F10, human MeWo, and human TXM13 cells. The B values of [ Cu]Cu-bispidine-NAP-NS1 ([ Cu]Cu-2) and [ Cu]Cu-DMPTACN-NAP-NS1 ([ Cu]Cu-3) were higher than those of [ Cu]Cu-NOTA-NAP-NS1 ([ Cu]Cu-1), implying that different charged chelate units might have an impact on binding capacity. Preliminary in vivo biodistribution studies suggested the main excretion pathway of [ Cu]Cu-1 and [ Cu]Cu-3 to be renal, while that of [ Cu]Cu-2 seemed to be both renal and hepatobiliary. An initial moderate uptake in the kidney decreased clearly after 60 minutes. All three Cu-labeled conjugates should be considered for further in vivo investigations using a suitable xenograft mouse model.
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http://dx.doi.org/10.1002/jlcr.3728DOI Listing
June 2019

Improved Conjugation, 64-Cu Radiolabeling, in Vivo Stability, and Imaging Using Nonprotected Bifunctional Macrocyclic Ligands: Bis(Phosphinate) Cyclam (BPC) Chelators.

J Med Chem 2018 10 24;61(19):8774-8796. Epub 2018 Sep 24.

Department of Inorganic Chemistry, Faculty of Science , Charles University , Hlavova 2030 , 128 40 Prague , Czech Republic.

Bifunctional derivatives of bis(phosphinate)-bearing cyclam (BPC) chelators bearing a carboxylate, amine, isothiocyanate, azide, or cyclooctyne in the BP side chain were synthesized. Conjugations required no protection of phosphinate or ring secondary amine groups. The ring amines were not reactive (proton protected) at pH < ∼8. For isothiocyanate coupling, oligopeptide N-terminal α-amines were more suitable than alkyl amines, e.g., Lys ω-amine (p K ∼7.5-8.5 and ∼10-11, respectively) due to lower basicity. The Cu-64 labeling was efficient at room temperature (specific activity ∼100 GBq/μmol; 25 °C, pH 6.2, ∼100 ligand equiv, 10 min). A representative Cu-64-BPC was tested in vivo showing fast clearance and no nonspecific radioactivity deposition. The monoclonal anti-PSCA antibody 7F5 conjugates with thiocyanate BPC derivative or NODAGA were radiolabeled and studied in PC3-PSCA tumor bearing mice by PET. The radiolabeled BPC conjugate was accumulated in the prostate tumor with a low off-target uptake, unlike Cu-64-labeled NODAGA-antibody conjugate. The BPC chelators have a great potential for theranostic applications of the Cu-64/Cu-67 matched pair.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00932DOI Listing
October 2018

Exploring pitfalls of Cu-labeled EGFR-targeting peptide GE11 as a potential PET tracer.

Amino Acids 2018 Oct 23;50(10):1415-1431. Epub 2018 Jul 23.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.

The epidermal growth factor receptor (EGFR) represents an important molecular target for both radiotracer-based diagnostic imaging and radionuclide therapy of various cancer entities. For the delivery of radionuclides to the tumor, peptides hold great potential as a transport vehicle. With respect to EGFR, the peptide YHWYGYTPQNVI (GE11) has been reported to bind the receptor with high specificity and affinity. In the present study, GE11 with β-alanine (β-Ala-GE11) was conjugated to the chelating agent p-SCN-Bn-NOTA and radiolabeled with Cu for the first radio pharmacological evaluation as a potential probe for positron emission tomography (PET)-based cancer imaging. For better water solubility, an ethylene glycol-based linker was introduced between the peptide's N terminus and the radionuclide chelator. The stability of the Cu-labeled peptide conjugate and its binding to EGFR-expressing tumor cells was investigated in vitro and in vivo, and then compared with the Cu-labeled EGFR-targeting antibody conjugate NOTA-cetuximab. The GE11 peptide conjugate [Cu]Cu-NOTA-linker-β-Ala-GE11 ([Cu]Cu-1) was stable in a buffer solution for at least 24 h but only 50% of the original compound was detected after 24 h of incubation in human serum. Stability could be improved by amidation of the peptide's C terminus (β-Ala-GE11-NH (2)). Binding assays with both conjugates, [Cu]Cu-1 and [Cu]Cu-2, using the EGFR-expressing tumor cell lines A431 and FaDu showed no specific binding. A pilot small animal PET investigation in FaDu tumor-bearing mice revealed only low tumor uptake (standard uptake value (SUV) < 0.2) for both conjugates. The best tumor-to-muscle ratio determined was 3.75 for [Cu]Cu-1, at 1 h post injection. In conclusion, the GE11 conjugates in its present form are not suitable for further biological investigations, since they presumably form aggregates.
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http://dx.doi.org/10.1007/s00726-018-2616-5DOI Listing
October 2018

Modified Calix[4]crowns as Molecular Receptors for Barium.

ChemistryOpen 2018 Jun 15;7(6):432-438. Epub 2018 May 15.

Institut für Radiopharmazeutische Krebsforschung Helmholtz-Zentrum Dresden-Rossendorf Bautzner Landstraße 400 01328 Dresden Germany.

A series of modified calix[4]crown-6 derivatives was synthesized to chelate the heavy group 2 metal barium, which serves as a non-radioactive surrogate for radium-223/-224; radionuclides with promising properties for radiopharmaceutical use. These calixcrowns were functionalized with either cyclic amide moieties or with deprotonizable groups, and the corresponding barium complexes were synthesized. Stability constants of these complexes were measured by using NMR and UV/Vis titration techniques to determine log values of >4.1. Further extraction studies were performed to characterize the binding affinity of calixcrowns to radioactive barium-133. Additionally, the ligands containing cyclic amides were investigated regarding their rotational barriers by using temperature-dependent NMR measurements.
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http://dx.doi.org/10.1002/open.201800019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987830PMC
June 2018

Modified Calix[4]crowns as Molecular Receptors for Barium.

ChemistryOpen 2018 Jun 15;7(6):431. Epub 2018 May 15.

Institut für Radiopharmazeutische Krebsforschung Helmholtz-Zentrum Dresden-Rossendorf Bautzner Landstraße 400 01328 Dresden Germany.

Invited for this month's cover picture is the group around Dr. Constantin Mamat at the Institute of Radiopharmaceutical Cancer Research at the Helmholtz-Zentrum Dresden-Rossendorf (Germany) together with Prof. Martin Köckerling from the University of Rostock (Germany). The cover picture shows the ability of special functionalized calix[4]crown-6 derivatives to stably bind group 2 metals like barium. This binding mode is highly important for radiopharmaceutical applications not to lose the respective radiometal in vivo to avoid high background signals and/or false positive results and damages in other tissues. For this purpose, different calix[4]crowns were tested, based upon their potential to stably bind barium as surrogate for radium. Radium nuclides are known to be good candidates for usage in α-targeted therapies. Currently, radium-223 is used for α-therapy of bone metastases because of its calcium mimetics. Our aim is to apply the radium to treat other cancer tissues. That's why we need novel chelators to stably fix groups 2 metals like barium and radium. Read the full text of their Full Paper at https://doi.org/10.1002/open.201800019.
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http://dx.doi.org/10.1002/open.201800065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987822PMC
June 2018

Synthesis, Characterization, and Initial Biological Evaluation of [ Tc]Tc-Tricarbonyl-labeled DPA-α-MSH Peptide Derivatives for Potential Melanoma Imaging.

ChemMedChem 2018 06 23;13(11):1146-1158. Epub 2018 Apr 23.

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328, Dresden, Germany.

α-Melanocyte stimulating hormone (α-MSH) derivatives target the melanocortin-1 receptor (MC1R) specifically and selectively. In this study, the α-MSH-derived peptide NAP-NS1 (Nle-Asp-His-d-Phe-Arg-Trp-Gly-NH ) with and without linkers was conjugated with 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid (DPA-COOH) and labeled with [ Tc]Tc-tricarbonyl by two methods. With the one-pot method the labeling was faster than with the two-pot method, while obtaining similarly high yields. Negligible trans-chelation and high stability in physiological solutions was determined for the [ Tc]Tc-tricarbonyl-peptide conjugates. Coupling an ethylene glycol (EG)-based linker increased the hydrophilicity. The peptide derivatives displayed high binding affinity in murine B16F10 melanoma cells as well as in human MeWo and TXM13 melanoma cell homogenates. Preliminary in vivo studies with one of the [ Tc]Tc-tricarbonyl-peptide conjugates showed good stability in blood and both renal and hepatobiliary excretion. Biodistribution was performed on healthy rats to gain initial insight into the potential relevance of the Tc-labeled peptides for in vivo imaging.
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http://dx.doi.org/10.1002/cmdc.201800110DOI Listing
June 2018

Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments.

Molecules 2018 02 17;23(2). Epub 2018 Feb 17.

Department Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany.

Experimental evidence has associated receptor tyrosine kinase EphB4 with tumor angiogenesis also in malignant melanoma. Considering the limited in vivo data available, we have conducted a systematic multitracer and multimodal imaging investigation in EphB4-overexpressing and mock-transfected A375 melanoma xenografts. Tumor growth, perfusion, and hypoxia were investigated by positron emission tomography. Vascularization was investigated by fluorescence imaging in vivo and ex vivo. The approach was completed by magnetic resonance imaging, radioluminography ex vivo, and immunohistochemical staining for blood and lymph vessel markers. Results revealed EphB4 to be a positive regulator of A375 melanoma growth, but a negative regulator of tumor vascularization. Resulting in increased hypoxia, this physiological characteristic is considered as highly unfavorable for melanoma prognosis and therapy outcome. Lymphangiogenesis, by contrast, was not influenced by EphB4 overexpression. In order to distinguish between EphB4 forward and EphrinB2, the natural EphB4 ligand, reverse signaling a specific EphB4 kinase inhibitor was applied. Blocking experiments show EphrinB2 reverse signaling rather than EphB4 forward signaling to be responsible for the observed effects. In conclusion, functional expression of EphB4 is considered a promising differentiating characteristic, preferentially determined by non-invasive in vivo imaging, which may improve personalized theranostics of malignant melanoma.
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http://dx.doi.org/10.3390/molecules23020444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017846PMC
February 2018

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform.

Oncoimmunology 2017;6(4):e1287246. Epub 2017 Feb 6.

Tumor Immunology, University Cancer Center (UCC), 'Carl Gustav Carus,' TU Dresden, Dresden, Germany.

Recent treatments of leukemias with chimeric antigen receptor (CAR) expressing T cells underline their impressive therapeutic potential. However, once adoptively transferred into patients, there is little scope left to shut them down after elimination of tumor cells or in case adverse side effects occur. This becomes of special relevance if they are directed against commonly expressed tumor associated antigens (TAAs) such as receptors of the ErbB family. To overcome this limitation, we recently established a modular CAR platform technology termed UniCAR. UniCARs are not directed against TAAs but instead against a unique peptide epitope on engineered recombinant targeting modules (TMs), which guide them to the target. In the absence of a TM UniCAR T cells are inactive. Thus an interruption of any UniCAR activity requires an elimination of unbound TM and the TM complexed with UniCAR T cells. Elimination of the latter one requires a disassembly of the UniCAR-TM complexes. Here, we describe a first nanobody (nb)-based TM directed against EGFR. The novel TM efficiently retargets UniCAR T cells to EGFR positive tumors and mediates highly efficient target-specific and target-dependent tumor cell lysis both and . After radiolabeling of the novel TM with Cu and Ga, we analyzed its biodistribution and clearance as well as the stability of the UniCAR-TM complexes. As expected unbound TM is rapidly eliminated while the elimination of the TM complexed with UniCAR T cells is delayed. Nonetheless, we show that UniCAR-TM complexes dissociate and in a concentration-dependent manner in line with the concept of a repeated stop and go retargeting of tumor cells via the UniCAR technology.
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http://dx.doi.org/10.1080/2162402X.2017.1287246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414885PMC
February 2017

Novel Tumor Pretargeting System Based on Complementary l-Configured Oligonucleotides.

Bioconjug Chem 2017 04 22;28(4):1176-1188. Epub 2017 Mar 22.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research , Bautzner Landstrasse 400, 01328 Dresden, Germany.

Unnatural mirror image l-configured oligonucleotides (L-ONs) are a convenient substance class for the application as complementary in vivo recognition system between a tumor specific antibody and a smaller radiolabeled effector molecule in pretargeting approaches. The high hybridization velocity and defined melting conditions are excellent preconditions of the L-ON based methodology. Their high metabolic stability and negligible unspecific binding to endogenous targets are superior characteristics in comparison to their d-configured analogs. In this study, a radiopharmacological evaluation of a new l-ONs based pretargeting system using the epidermal growth factor receptor (EGFR) specific antibody cetuximab (C225) as target-seeking component is presented. An optimized PEGylated 17mer-L-DNA was conjugated with p-SCN-Bn-NOTA (NOTA') to permit radiolabeling with the radionuclide Cu. C225 was modified with the complementary 17mer-L-DNA (c-L-DNA) strand as well as with NOTA' for radiolabeling and use for positron emission tomography (PET). Two C225 conjugates were coupled with 1.5 and 5.0 c-L-DNA molecules, respectively. In vitro characterization was done with respect to hybridization studies, competition and saturation binding assays in EGFR expressing squamous cell carcinoma cell lines A431 and FaDu. The modified C225 derivatives exhibited high binding affinities in the low nanomolar range to the EGFR. PET and biodistribution experiments on FaDu tumor bearing mice with directly Cu-labeled NOTA'-C225-(c-L-DNA) conjugate revealed that a pretargeting interval of 24 h might be a good compromise between tumor accumulation, internalization, blood background, and liver uptake of the antibody. Despite internalization of the antibody in vivo pretargeting experiments showed an adequate hybridization of Cu-radiolabeled NOTA'-L-DNA to the tumor located antibody and a good tumor-to-muscle ratio of about 11 resulting in a clearly visible image of the tumor after 24 h up to 72 h. Furthermore, low accumulation of radioactivity in organs responsible for metabolism and excretion was determined. The presented results indicate a high potential of complementary L-ONs for the pretargeting approach which can also be applied to therapeutic radionuclides such as Lu, Y, Re, or Re.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00045DOI Listing
April 2017

New insights into the pretargeting approach to image and treat tumours.

Chem Soc Rev 2016 Nov;45(23):6415-6431

Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

Tumour pretargeting is a promising strategy for cancer diagnosis and therapy allowing for the rational use of long circulating, highly specific monoclonal antibodies (mAbs) for both non-invasive cancer radioimmunodetection (RID) and radioimmunotherapy (RIT). In contrast to conventional RID/RIT where the radionuclides and oncotropic vector molecules are delivered as presynthesised radioimmunoconjugates, the pretargeting approach is a multistep procedure that temporarily separates targeting of certain tumour-associated antigens from delivery of diagnostic or therapeutic radionuclides. In principle, unlabelled, highly tumour antigen specific mAb conjugates are, in a first step, administered into a patient. After injection, sufficient time is allowed for blood circulation, accumulation at the tumour site and subsequent elimination of excess mAb conjugates from the body. The small fast-clearing radiolabelled effector molecules with a complementary functionality directed to the prelocalised mAb conjugates are then administered in a second step. Due to its fast pharmacokinetics, the small effector molecules reach the malignant tissue quickly and bind the local mAb conjugates. Thereby, corresponding radioimmunoconjugates are formed in vivo and, consequently, radiation doses are deposited mainly locally. This procedure results in a much higher tumour/non-tumour (T/NT) ratio and is favourable for cancer diagnosis and therapy as it substantially minimises the radiation damage to non-tumour cells of healthy tissues. The pretargeting approach utilises specific non-covalent interactions (e.g. strept(avidin)/biotin) or covalent bond formations (e.g. inverse electron demand Diels-Alder reaction) between the tumour bound antibody and radiolabelled small molecules. This tutorial review descriptively presents this complex strategy, addresses the historical as well as recent preclinical and clinical advances and discusses the advantages and disadvantages of different available variations.
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http://dx.doi.org/10.1039/c5cs00784dDOI Listing
November 2016

Melanoma targeting with [Tc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analogs: Effects of cyclization on the radiopharmaceutical properties.

Nucl Med Biol 2016 Dec 31;43(12):788-801. Epub 2016 Aug 31.

ICMATE-CNR, Corso Stati Uniti 4, 35127, Padova, Italy. Electronic address:

The purpose of this study was to evaluate the effect of cyclization on the biological profile of a [Tc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analog. A lactam bridge-cyclized H-Cys-Ahx-βAla-c[Lys-Glu-His-D-Phe-Arg-Trp-Glu]-Arg-Pro-Val-NH (NAP-NS2) and the corresponding linear H-Cys-Ahx-βAla-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH (NAP-NS1) peptide were synthetized, characterized by ESI-MS spectroscopy and their melanocortin-1 receptor (MC1R) binding affinity was determined in B16/F10 melanoma cells. The consistent [Tc(N)(PNP3)]-labeled compounds were readily obtained in high specific activity and their stability and biological properties were assessed. As an example, the chemical identity of [Tc(N)(NAP-NS1)(PNP3)] was confirmed by carrier added experiments supported by radio/UV HPLC analysis combined with ESI(+)-MS. Compared with the linear peptide, cyclization negatively affected the biological properties of NAP-NS2 peptide by reducing its binding affinity for MC1R and by decreasing the overall excretion rate of the corresponding [Tc(N)(PNP3)]-labeled peptide from the body as well as its in vivo stability. [Tc(N)(NAP-NS1)(PNP3)] was evaluated for its potential as melanoma imaging probe in murine melanoma model. Data from in vitro and in vivo studies on B16/F10 melanoma model of [Tc(N)(NAP-NS1)(PNP3)] clearly evidenced that the radiolabeled linear peptide keeps its biological properties up on the conjugation to the [Tc(N)(PNP3)]-building block. The progressive increase of the tumor-to-nontarget ratios over the time indicates a quite stable interaction between the radio-complex and the MC1R.
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http://dx.doi.org/10.1016/j.nucmedbio.2016.08.014DOI Listing
December 2016

Radiopharmacological characterization of ⁶⁴Cu-labeled α-MSH analogs for potential use in imaging of malignant melanoma.

Amino Acids 2016 Mar 7;48(3):833-847. Epub 2015 Dec 7.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.

The melanocortin-1 receptor (MC1R) plays an important role in melanoma growth, angiogenesis and metastasis, and is overexpressed in melanoma cells. α-Melanocyte stimulating hormone (α-MSH) and derivatives are known to bind with high affinity at this receptor that provides the potential for selective targeting of melanoma. In this study, one linear α-MSH-derived peptide Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2 (NAP-NS1) without linker and with εAhx-β-Ala linker, and a cyclic α-MSH derivative, [Lys-Glu-His-D-Phe-Arg-Trp-Glu]-Arg-Pro-Val-NH2 (NAP-NS2) with εAhx-β-Ala linker were conjugated with p-SCN-Bn-NOTA and labeled with (64)Cu. Radiochemical and radiopharmacological investigations were performed with regard to transchelation, stability, lipophilicity and in vitro binding assays as well as biodistribution in healthy rats. No transchelation reactions, but high metabolic stability and water solubility were demonstrated. The linear derivatives showed higher affinity than the cyclic one. [(64)Cu]Cu-NOTA-εAhx-β-Ala-NAP-NS1 ([(64)Cu]Cu-2) displayed rapid cellular association and dissociation in murine B16F10 cell homogenate. All [(64)Cu]Cu-labeled conjugates exhibited affinities in the low nanomolar range in B16F10. [(64)Cu]Cu-2 showed also high affinity in human MeWo and TXM13 cell homogenate. In vivo studies suggested that [(64)Cu]Cu-2 was stable, with about 85 % of intact peptide in rat plasma at 2 h p.i. Biodistribution confirmed the renal pathway as the major elimination route. The uptake of [(64)Cu]Cu-2 in the kidney was 5.9 % ID/g at 5 min p.i. and decreased to 2.0 % ID/g at 60 min p.i. Due to the prospective radiochemical and radiopharmacological properties of the linear α-MSH derivative [(64)Cu]Cu-2, this conjugate is a promising candidate for tracer development in human melanoma imaging.
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http://dx.doi.org/10.1007/s00726-015-2131-xDOI Listing
March 2016

Cyclam Derivatives with a Bis(phosphinate) or a Phosphinato-Phosphonate Pendant Arm: Ligands for Fast and Efficient Copper(II) Complexation for Nuclear Medical Applications.

Inorg Chem 2015 Dec 25;54(24):11751-66. Epub 2015 Nov 25.

Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague , Hlavova 2030, 12840 Prague, Czech Republic.

Cyclam derivatives bearing one geminal bis(phosphinic acid), -CH2PO2HCH2PO2H2 (H2L(1)), or phosphinic-phosphonic acid, -CH2PO2HCH2PO3H2 (H3L(2)), pendant arm were synthesized and studied as potential copper(II) chelators for nuclear medical applications. The ligands showed good selectivity for copper(II) over zinc(II) and nickel(II) ions (log KCuL = 25.8 and 27.7 for H2L(1) and H3L(2), respectively). Kinetic study revealed an unusual three-step complex formation mechanism. The initial equilibrium step leads to out-of-cage complexes with Cu(2+) bound by the phosphorus-containing pendant arm. These species quickly rearrange to an in-cage complex with cyclam conformation II, which isomerizes to another in-cage complex with cyclam conformation I. The first in-cage complex is quantitatively formed in seconds (pH ≈5, 25 °C, Cu:L = 1:1, cM ≈ 1 mM). At pH >12, I isomers undergo nitrogen atom inversion, leading to III isomers; the structure of the III-[Cu(HL(2))] complex in the solid state was confirmed by X-ray diffraction analysis. In an alkaline solution, interconversion of the I and III isomers is mutual, leading to the same equilibrium isomeric mixture; such behavior has been observed here for the first time for copper(II) complexes of cyclam derivatives. Quantum-chemical calculations showed small energetic differences between the isomeric complexes of H3L(2) compared with analogous data for isomeric complexes of cyclam derivatives with one or two methylphosphonic acid pendant arm(s). Acid-assisted dissociation proved the kinetic inertness of the complexes. Preliminary radiolabeling of H2L(1) and H3L(2) with (64)Cu was fast and efficient, even at room temperature, giving specific activities of around 70 GBq of (64)Cu per 1 μmol of the ligand (pH 6.2, 10 min, ca. 90 equiv of the ligand). These specific activities were much higher than those of H3nota and H4dota complexes prepared under identical conditions. The rare combination of simple ligand synthesis, very fast copper(II) complex formation, high thermodynamic stability, kinetic inertness, efficient radiolabeling, and expected low bone tissue affinity makes such ligands suitably predisposed to serve as chelators of copper radioisotopes in nuclear medicine.
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http://dx.doi.org/10.1021/acs.inorgchem.5b01791DOI Listing
December 2015

demonstration of an active tumor pretargeting approach with peptide nucleic acid bioconjugates as complementary system.

Chem Sci 2015 Oct 17;6(10):5601-5616. Epub 2015 Jun 17.

Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: ; http://www.gassergroup.com ; Tel: +41 44 635 46 30.

A novel, promising strategy for cancer diagnosis and therapy is the use of a pretargeting approach. For this purpose, the non-natural DNA/RNA analogues Peptide Nucleic Acids (PNAs) are ideal candidates as recognition units due to their high metabolic stability and lack of unspecific accumulation. In the pretargeting approach, an unlabeled, highly specific antibody-PNA conjugate has sufficient time to target a tumor before administration of a small fast-clearing radiolabeled complementary PNA that hybridizes with the antibody-PNA conjugate at the tumor site. Herein, we report the first successful application of this multistep process using a PNA-modified epidermal growth factor receptor (EGFR) specific antibody (cetuximab) and a complementary Tc-labeled PNA. studies on tumor bearing mice demonstrated a rapid and efficient hybridization of the radiolabeled PNA with the antibody-PNA conjugate. Decisively, a high specific tumor accumulation was observed with a tumor-to-muscle ratio of >8, resulting in a clear visualization of the tumor by single photon emission computed tomography (SPECT).
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http://dx.doi.org/10.1039/c5sc00951kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949856PMC
October 2015

Bifunctional cyclam-based ligands with phosphorus acid pendant moieties for radiocopper separation: thermodynamic and kinetic studies.

Chemistry 2015 Mar 3;21(12):4671-87. Epub 2015 Feb 3.

Department of Inorganic Chemistry, Faculty of Science, Universita Karlova (Charles University), Hlavova 2030, 12840 Prague 2 (Czech Republic).

Two macrocyclic ligands based on cyclam with trans-disposed N-methyl and N-(4-aminobenzyl) substituents as well as two methylphosphinic (H2L1) or methylphosphonic (H4L2) acid pendant arms were synthesised and investigated in solution. The ligands form stable complexes with transition metal ions. Both ligands show high thermodynamic selectivity for divalent copper over nickel(II) and zinc(II)-K(CuL) is larger than K(Ni/ZnL) by about seven orders of magnitude. Complexation is significantly faster for the phosphonate ligand H4L2, probably due to the stronger coordination ability of the more basic phosphonate groups, which efficiently bind the metal ion in an "out-of-cage" complex and thus accelerate its "in-cage" binding. The rate of Cu(II) complexation by the phosphinate ligand H2L1 is comparable to that of cyclam itself and its derivatives with non-coordinating substituents. Acid-assisted decomplexation of the copper(II) complexes is relatively fast (τ1/2 = 44 and 42 s in 1 M aq. HClO4 at 25 °C for H2L1 and H4L2, respectively). This combination of properties is convenient for selective copper removal/purification. Thus, the title ligands were employed in the preparation of ion-selective resins for radiocopper(II) separation. Glycidyl methacrylate copolymer beads were modified with the ligands through a diazotisation reaction. The separation ability of the modified polymers was tested with cold copper(II) and non-carrier-added (64)Cu in the presence of a large excess of both nickel(II) and zinc(II). The experiments exhibited high overall separation efficiency leading to 60-70% recovery of radiocopper with high selectivity over the other metal ions, which were originally present in 900-fold molar excess. The results showed that chelating resins with properly tuned selectivity of their complexing moieties can be employed for radiocopper separation.
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http://dx.doi.org/10.1002/chem.201405777DOI Listing
March 2015

Theranostic mercury: (197(m))Hg with high specific activity for imaging and therapy.

Appl Radiat Isot 2015 Mar 5;97:177-181. Epub 2015 Jan 5.

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany.

The no carrier added (NCA) radionuclide (197(m))Hg is accessible through proton induced nuclear reactions on gold. The decay properties of both simultaneous produced nuclear isomers (197m)Hg and (197)Hg like convenient half life, low energy gamma radiations for imaging, Auger and conversion electrons for therapy are combined with unique chemical and physical properties of mercury and its compounds. Gold as a monoisotopic element has a natural abundance of 100% (197)Au superseding expensive enrichment for the target material. Additionally, the high thermal conductivity of gold enables high beam current irradiations. For separation of target material a liquid-liquid extraction method was applied.
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http://dx.doi.org/10.1016/j.apradiso.2015.01.001DOI Listing
March 2015

Polyoxometalates--potent and selective ecto-nucleotidase inhibitors.

Biochem Pharmacol 2015 Jan 13;93(2):171-81. Epub 2014 Nov 13.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address:

Polyoxometalates (POMs) are inorganic cluster metal complexes that possess versatile biological activities, including antibacterial, anticancer, antidiabetic, and antiviral effects. Their mechanisms of action at the molecular level are largely unknown. However, it has been suggested that the inhibition of several enzyme families (e.g., phosphatases, protein kinases or ecto-nucleotidases) by POMs may contribute to their pharmacological properties. Ecto-nucleotidases are cell membrane-bound or secreted glycoproteins involved in the hydrolysis of extracellular nucleotides thereby regulating purinergic (and pyrimidinergic) signaling. They comprise four distinct families: ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs), alkaline phosphatases (APs) and ecto-5'-nucleotidase (eN). In the present study, we evaluated the inhibitory potency of a series of polyoxometalates as well as chalcogenide hexarhenium cluster complexes at a broad range of ecto-nucleotidases. [Co4(H2O)2(PW9O34)2](10-) (5, PSB-POM142) was discovered to be the most potent inhibitor of human NTPDase1 described so far (Ki: 3.88 nM). Other investigated POMs selectively inhibited human NPP1, [TiW11CoO40](8-) (4, PSB-POM141, Ki: 1.46 nM) and [NaSb9W21O86](18-) (6, PSB-POM143, Ki: 4.98 nM) representing the most potent and selective human NPP1 inhibitors described to date. [NaP5W30O110](14-) (8, PSB-POM144) strongly inhibited NTPDase1-3 and NPP1 and may therefore be used as a pan-inhibitor to block ATP hydrolysis. The polyoxoanionic compounds displayed a non-competitive mechanism of inhibition of NPPs and eN, but appeared to be competitive inhibitors of TNAP. Future in vivo studies with selected inhibitors identified in the current study are warranted.
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http://dx.doi.org/10.1016/j.bcp.2014.11.002DOI Listing
January 2015

Assessment of the best N(3-) donors in preparation of [M(N)(PNP)]-based (M=(99m)Tc-; (188)Re) target-specific radiopharmaceuticals: Comparison among succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ).

Nucl Med Biol 2014 Aug 24;41(7):570-81. Epub 2014 Apr 24.

IENI-CNR, Corso Stati Uniti 4, 35127 Padova, Italy. Electronic address:

Succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ) are nitrido nitrogen atom donors employed for the preparation of nitride [M(N)]-complexes (M=(99m)Tc and (188)Re). This study aims to compare the capability and the efficiency of these three N(3-) group donors, in the preparation of [M(N)PNP]-based target-specific compounds (M=(99m)Tc, (188)Re; PNP=aminodiphosphine). For this purpose, three different kit formulations (SDH kit; HO2C-PEG600-DTCZ kit; HDTCZ kit) were assembled and used in the preparation of [M(N)(cys~)(PNP3)](0/+) complexes (cys~=cysteine derivate ligands). For each formulation, the radiochemical yield (RCY) of the [M(N)(~cys)(PNP3)] compounds, was determined by HPLC. The deviation of the percentage of RCY, due to changes in concentration of the N(3-) donors and of the exchanging ligand, was determined. For (99m)Tc, data clearly show that HDTCZ is the most efficient donor of N(3-); however, SDH is the most suitable nitrido nitrogen atom donor for the preparation of [(99m)Tc(N)(PNP)]-based target-specific agents with high specific activity. When HO2C-PEG600-DTCZ or HDTCZ are used in N(3-) donation, high amounts of the exchanging ligand (10(-4)M) were required for the formation of the final complex in acceptable yield. The possibility to use microgram amounts of HDTCZ also in [(188)Re(N)] preparation (0.050mg) reduces its ability to compete in ligand exchange reactions, minimizing the quantity of chelators required to obtain the final complex in high yield. This finding can be exploit for increasing the radiolabeling efficiency in [(188)Re(N)]-radiopharmaceutical preparations compared to the previously reported HDTCZ-based procedure, notwithstanding a purification process could be necessary to improve the specific activity of the complexes.
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http://dx.doi.org/10.1016/j.nucmedbio.2014.04.126DOI Listing
August 2014

Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy.

Pharmaceuticals (Basel) 2014 Mar 5;7(3):311-38. Epub 2014 Mar 5.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, Dresden 01328, Germany.

The epidermal growth factor receptor (EGFR) has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a) chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b) with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment.
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http://dx.doi.org/10.3390/ph7030311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978494PMC
March 2014

Cytotoxic properties of radionuclide-conjugated Cetuximab without and in combination with external irradiation in head and neck cancer cells in vitro.

Int J Radiat Biol 2014 Aug 3;90(8):678-86. Epub 2014 Apr 3.

OncoRay - National Center for Radiation Research in Oncology, Medizinische Fakultät Carl Gustav Carus.

Purpose: Epidermal growth factor receptor (EGFR) is critically involved in progression and therapy resistance of squamous cell carcinoma (SCC). Albeit EGFR targeting could improve the effect of radiotherapy on patients' outcome, the clinical results failed to meet expectations from preclinical studies. In this work, we evaluated the potential of the radionuclide Yttrium-90 ((90)Y) bound to Cetuximab ((90)Y-Cetuximab) as novel targeting approach for SCC cells in vitro.

Materials And Methods: FaDu and A431 cell lines were used. EGFR subcellular localization, clonogenic survival, radiation-induced γH2AX foci and EGFR signaling were examined. Cells were treated with DTPA, DTPA-Cetuximab, (90)Y and (90)Y-Cetuximab alone or in combination with external X-ray irradiation.

Results: Dose- and cell line-dependently, (90)Y-Cetuximab mediated a significant reduction in clonogenicity relative to unbound (90)Y. Combined 2-Gy external radiation plus 2-Gy equivalent dose of (90)Y-Cetuximab was more effective than equivalent doses of (90)Y and X-ray radiation. Analogous effects were observed in the number of residual radiation-induced foci. Additionally, EGFR, ERK1/2 and AKT phosphorylation showed alterations upon different treatments.

Conclusions: Our findings show that Cetuximab-conjugated (90)Y has a significant potential to eradicate human SCC cells. A combination of radioimmunotherapeutic compounds and external radiotherapy might be a promising treatment strategy for clinical application.
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http://dx.doi.org/10.3109/09553002.2014.899446DOI Listing
August 2014

Radiolabeled anti-EGFR-antibody improves local tumor control after external beam radiotherapy and offers theragnostic potential.

Radiother Oncol 2014 Feb 16;110(2):362-9. Epub 2014 Jan 16.

Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden - Rossendorf, Germany; German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Purpose: The effect of radioimmunotherapy (RIT) using the therapeutic radionuclide Y-90 bound to the anti-EGFR antibody cetuximab combined with external beam irradiation (EBRT) (EBRIT) on permanent local tumor control in vivo was examined.

Methods: Growth delay was evaluated in three human squamous cell carcinoma models after RIT with [(90)Y]Y-(CHX-A''-DTPA)₄-cetuximab (Y-90-cetuximab). The EBRT dose required to cure 50% of the tumors (TCD₅₀) for EBRT alone or EBRIT was evaluated in one RIT-responder (FaDu) and one RIT-non-responder (UT-SCC-5). EGFR expression and microenvironmental parameters were evaluated in untreated tumors, bioavailability was visualized by PET using ([(86)Y]Y-(CHX-A''-DTPA)₄-cetuximab (Y-86-cetuximab) and biodistribution using Y-90-cetuximab.

Results: In UT-SCC-8 and FaDu but not in UT-SCC-5 radiolabeled cetuximab led to significant tumor growth delay. TCD₅₀ after EBRT was significantly decreased by EGFR-targeted RIT in FaDu but not in UT-SCC-5. In contrast to EGFR expression, parameters of the tumor micromilieu and in particular the Y-90-cetuximab biodistribution or Y-86-cetuximab visualization in PET correlated with the responsiveness to RIT or EBRIT.

Conclusion: EGFR-targeted EBRIT can improve permanent local tumor control compared to EBRT alone. PET imaging of bioavailability of labeled cetuximab appears to be a suitable predictor for response to EBRIT. This theragnostic approach should be further explored for clinical translation.
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http://dx.doi.org/10.1016/j.radonc.2013.12.001DOI Listing
February 2014