Research

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12 pages, 2843 KiB

Open AccessArticle

Functionalization of ⁶⁸Ga-Radiolabeled Nanodiamonds with Octreotide Does Not Improve Tumor-Targeting Capabilities

by Thomas Wanek, Marco Raabe, Md Noor A Alam, Thomas Filip, Johann Stanek, Mathilde Loebsch, Christian Laube, Severin Mairinger, Tanja Weil and Claudia Kuntner

Pharmaceuticals 2024, 17(4), 514; https://doi.org/10.3390/ph17040514 - 17 Apr 2024

Viewed by 275

Abstract

Nanodiamonds (NDs) are emerging as a novel nanoparticle class with growing interest in medical applications. The surface coating of NDs can be modified by attaching binding ligands or imaging probes, turning them into multi-modal targeting agents. In this investigation, we assessed the targeting [...] Read more.

Nanodiamonds (NDs) are emerging as a novel nanoparticle class with growing interest in medical applications. The surface coating of NDs can be modified by attaching binding ligands or imaging probes, turning them into multi-modal targeting agents. In this investigation, we assessed the targeting efficacy of octreotide-functionalized ⁶⁸Ga-radiolabelled NDs for cancer imaging and compared it with the tumor uptake using [⁶⁸Ga]Ga-DOTA-TOC. In vivo studies in mice bearing AR42J tumors demonstrated the highest accumulation of the radiolabeled functionalized NDs in the liver and spleen, with relatively low tumor uptake compared to [⁶⁸Ga]Ga-DOTA-TOC. Our findings suggest that, within the scope of this study, functionalization did not enhance the tumor-targeting capabilities of NDs. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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28 pages, 32029 KiB

Open AccessArticle

Target Development towards First Production of High-Molar- Activity ^44gSc and ⁴⁷Sc by Mass Separation at CERN-MEDICIS

by Edgars Mamis, Charlotte Duchemin, Valentina Berlin, Cyril Bernerd, Mathieu Bovigny, Eric Chevallay, Bernard Crepieux, Vadim Maratovich Gadelshin, Reinhard Heinke, Ronaldo Mendez Hernandez, Jake David Johnson, Patrīcija Kalniņa, Alexandros Koliatos, Laura Lambert, Ralf Erik Rossel, Sebastian Rothe, Julien Thiboud, Felix Weber, Klaus Wendt, Rudolfs Jānis Zabolockis, Elīna Pajuste and Thierry Stora Show full author list Hide full author list

Pharmaceuticals 2024, 17(3), 390; https://doi.org/10.3390/ph17030390 - 18 Mar 2024

Viewed by 895

Abstract

The radionuclides ⁴³Sc,

^{44 g / m}

Sc, and ⁴⁷Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating

^{n a t}

Ti and

^{n a t}

V target materials with protons. Maximizing [...] Read more.

The radionuclides ⁴³Sc,

^{44 g / m}

Sc, and ⁴⁷Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating

^{n a t}

Ti and

^{n a t}

V target materials with protons. Maximizing the production yield of the therapeutic ⁴⁷Sc in the highest cross section energy range of 24–70 MeV results in the co-production of long-lived, high-

γ

-ray-energy ⁴⁶Sc and ⁴⁸Sc contaminants if one does not use enriched target materials. Mass separation can be used to obtain high molar activity and isotopically pure Sc radionuclides from natural target materials; however, suitable operational conditions to obtain relevant activity released from irradiated

^{n a t}

Ti and

^{n a t}

V have not yet been established at CERN-MEDICIS and ISOLDE. The objective of this work was to develop target units for the production, release, and purification of Sc radionuclides by mass separation as well as to investigate target materials for the mass separation that are compatible with high-yield Sc radionuclide production in the 9–70 MeV proton energy range. In this study, the in-target production yield obtained at MEDICIS with 1.4 GeV protons is compared with the production yield that can be reached with commercially available cyclotrons. The thick-target materials were irradiated at MEDICIS and comprised of metallic

^{n a t}

Ti,

^{n a t}

V metallic foils, and

^{n a t}

TiC pellets. The produced radionuclides were subsequently released, ionized, and extracted from various target and ion source units and mass separated. Mono-atomic Sc laser and molecule ionization with forced-electron-beam-induced arc-discharge ion sources were investigated. Sc radionuclide production in thick

^{n a t}

Ti and

^{n a t}

V targets at MEDICIS is equivalent to low- to medium-energy cyclotron-irradiated targets at medically relevant yields, furthermore benefiting from the mass separation possibility. A two-step laser resonance ionization scheme was used to obtain mono-atomic Sc ion beams. Sc radionuclide release from irradiated target units most effectively could be promoted by volatile scandium fluoride formation. Thus, isotopically pure

^{44 g / m}

Sc, ⁴⁶Sc, and ⁴⁷Sc were obtained as mono-atomic and molecular ScF

_{2}^{+}

ion beams and collected for the first time at CERN-MEDICIS. Among all the investigated target materials,

^{n a t}

TiC is the most suitable target material for Sc mass separation as molecular halide beams, due to high possible operating temperatures and sustained release. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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13 pages, 6473 KiB

Open AccessArticle

Innovative Approach to Producing Palladium-103 for Auger-Emitting Radionuclide Therapy: A Proof-of-Concept Study

by Aicha Nour Laouameria, Mátyás Hunyadi, Attila Csík and Zoltán Szűcs

Pharmaceuticals 2024, 17(2), 253; https://doi.org/10.3390/ph17020253 - 16 Feb 2024

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Abstract

Auger-emitting radionuclides, exemplified by Pd-103, exhibit considerable therapeutic potential in cancer treatment due to their high cytotoxicity and localized biological impact. Despite these advantages, the separation of such radionuclides presents a complicated challenge, requiring intricate and time-intensive “wet chemistry” methods attributed to the [...] Read more.

Auger-emitting radionuclides, exemplified by Pd-103, exhibit considerable therapeutic potential in cancer treatment due to their high cytotoxicity and localized biological impact. Despite these advantages, the separation of such radionuclides presents a complicated challenge, requiring intricate and time-intensive “wet chemistry” methods attributed to the exceptional chemical inertness of the associated metals. This study proposes an innovative solution to this separation challenge through the design and implementation of a piece of radionuclide separation equipment (RSE). The equipment employs a dry distillation approach, capitalizing on differences in partial vapor pressures between irradiated and resulting radioactive metals, with a diffusion-driven extraction method applied to separate Pd-103 radionuclides generated via the proton irradiation of Rh-103 at cyclotron. Our optimization endeavors focused on determining the optimal temperature for effective metal separation and adjusting the diffusion, evaporation, and deposition rates, as well as addressing chemical impurities. The calculations indicate 17% ± 2% separation efficiency with our RSE. Approximately 77 ± 2% and 49 ± 2% of the deposited Pd-103 were isolated on substrates of Nb foil and ZnO-covered W disc, respectively. The proposed innovative dry distillation method that has been experimentally tested offers a promising alternative to conventional separation techniques, enabling enhanced purity and cost-efficient cancer treatment strategies. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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14 pages, 3903 KiB

Open AccessArticle

Nuclear Cross-Section of Proton-Induced Reactions on Enriched ⁴⁸Ti Targets for the Production of Theranostic ⁴⁷Sc Radionuclide, ^46cSc, ^44mSc, ^44gSc, ⁴³Sc, and ⁴⁸V

by Liliana Mou, Lucia De Dominicis, Sara Cisternino, Hanna Skliarova, Matteo Campostrini, Valentino Rigato, Laura De Nardo, Laura Meléndez-Alafort, Juan Esposito, Férid Haddad and Gaia Pupillo

Pharmaceuticals 2024, 17(1), 26; https://doi.org/10.3390/ph17010026 - 23 Dec 2023

Viewed by 757

Abstract

The cross-sections of the ⁴⁸Ti(p,x)⁴⁷Sc, ^46cSc, ^44mSc, ^44gSc, ⁴³Sc, and ⁴⁸V nuclear reactions were measured from 18 to 70 MeV, with particular attention to ⁴⁷Sc production. Enriched ⁴⁸Ti powder was deposited on an [...] Read more.

The cross-sections of the ⁴⁸Ti(p,x)⁴⁷Sc, ^46cSc, ^44mSc, ^44gSc, ⁴³Sc, and ⁴⁸V nuclear reactions were measured from 18 to 70 MeV, with particular attention to ⁴⁷Sc production. Enriched ⁴⁸Ti powder was deposited on an aluminum backing and the obtained targets were characterized via elastic backscattering spectroscopy at the INFN-LNL. Targets were exposed to low-intensity proton irradiation using the stacked-foils technique at the ARRONAX facility. Activated samples were measured using γ-spectrometry; the results were compared with the data int he literature and the theoretical TALYS-based values. A regular trend in the new values obtained from the different irradiation runs was noted, as well as a good agreement with the literature data, for all the radionuclides of interest: ⁴⁷Sc, ^46cSc, ^44mSc, ^44gSc, ⁴³Sc, and ⁴⁸V. ⁴⁷Sc production was also discussed, considering yield and radionuclidic purity, for different ⁴⁷Sc production scenarios. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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14 pages, 1845 KiB

Open AccessArticle

Novel Auger-Electron-Emitting ¹⁹¹Pt-Labeled Pyrrole–Imidazole Polyamide Targeting MYCN Increases Cytotoxicity and Cytosolic dsDNA Granules in MYCN-Amplified Neuroblastoma

by Honoka Obata, Atsushi B. Tsuji, Hitomi Sudo, Aya Sugyo, Kaori Hashiya, Hayato Ikeda, Masatoshi Itoh, Katsuyuki Minegishi, Kotaro Nagatsu, Mikako Ogawa, Toshikazu Bando, Hiroshi Sugiyama and Ming-Rong Zhang

Pharmaceuticals 2023, 16(11), 1526; https://doi.org/10.3390/ph16111526 - 27 Oct 2023

Viewed by 1180

Abstract

Auger electrons can cause nanoscale physiochemical damage to specific DNA sites that play a key role in cancer cell survival. Radio-Pt is a promising Auger-electron source for damaging DNA efficiently because of its ability to bind to DNA. Considering that the cancer genome [...] Read more.

Auger electrons can cause nanoscale physiochemical damage to specific DNA sites that play a key role in cancer cell survival. Radio-Pt is a promising Auger-electron source for damaging DNA efficiently because of its ability to bind to DNA. Considering that the cancer genome is maintained under abnormal gene amplification and expression, here, we developed a novel ¹⁹¹Pt-labeled agent based on pyrrole–imidazole polyamide (PIP), targeting the oncogene MYCN amplified in human neuroblastoma, and investigated its targeting ability and damaging effects. A conjugate of MYCN-targeting PIP and Cys-(Arg)₃-coumarin was labeled with ¹⁹¹Pt via Cys (¹⁹¹Pt-MYCN-PIP) with a radiochemical purity of >99%. The binding potential of ¹⁹¹Pt-MYCN-PIP was evaluated via the gel electrophoretic mobility shift assay, suggesting that the radioagent bound to the DNA including the target sequence of the MYCN gene. In vitro assays using human neuroblastoma cells showed that ¹⁹¹Pt-MYCN-PIP bound to DNA efficiently and caused DNA damage, decreasing MYCN gene expression and MYCN signals in in situ hybridization analysis, as well as cell viability, especially in MYCN-amplified Kelly cells. ¹⁹¹Pt-MYCN-PIP also induced a substantial increase in cytosolic dsDNA granules and generated proinflammatory cytokines, IFN-α/β, in Kelly cells. Tumor uptake of intravenously injected ¹⁹¹Pt-MYCN-PIP was low and its delivery to tumors should be improved for therapeutic application. The present results provided a potential strategy, targeting the key oncogenes for cancer survival for Auger electron therapy. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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17 pages, 3239 KiB

Open AccessArticle

Radionuclide Cisternography with [⁶⁴Cu]Cu-DOTA

by Julia Greiser, Sebastian Groeber, Thomas Weisheit, Tobias Niksch, Matthias Schwab, Christian Senft, Christian Kuehnel, Robert Drescher and Martin Freesmeyer

Pharmaceuticals 2023, 16(9), 1269; https://doi.org/10.3390/ph16091269 - 07 Sep 2023

Cited by 3 | Viewed by 904

Abstract

Radionuclide cisternography (RNC) is a method for conducting imaging of the cerebrospinal system and can be used to identify cerebrospinal fluid leaks. So far, RNC has commonly employed radiopharmaceutical agents suitable only for single-photon emission tomography techniques, which are thus lacking in terms [...] Read more.

Radionuclide cisternography (RNC) is a method for conducting imaging of the cerebrospinal system and can be used to identify cerebrospinal fluid leaks. So far, RNC has commonly employed radiopharmaceutical agents suitable only for single-photon emission tomography techniques, which are thus lacking in terms of image resolution and can potentially lead to false-negative results. Therefore, [⁶⁴Cu]Cu-DOTA was investigated as an alternative radiopharmaceutical for RNC, employing positron emission tomography (PET) instead of single-photon emission tomography. A formulation of [⁶⁴Cu]Cu-DOTA was produced according to the guidelines for good manufacturing practice. The product met the requirements of agents suitable for intrathecal application. [⁶⁴Cu]Cu-DOTA was administered to a patient and compared to the approved scintigraphic RNC agent, [¹¹¹In]In-DTPA. While no cerebrospinal fluid leak was detected with [¹¹¹In]In-DTPA, [⁶⁴Cu]Cu-DOTA RNC exhibited a posterolateral leak between the vertebral bodies C1 and C2. Thus, in this patient, PET RNC with [⁶⁴Cu]Cu-DOTA was superior to RNC with [¹¹¹In]In-DTPA. Since radiopharmaceuticals have a very good safety profile regarding the occurrence of adverse events, PET RNC with [⁶⁴Cu]Cu-DOTA may become an attractive alternative to scintigraphic methods, and also to computed tomography or magnetic resonance imaging, which often require contrast agents, causing adverse events to occur much more frequently. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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12 pages, 1307 KiB

Open AccessArticle

Cyclotron-Based Production of ⁶⁷Cu for Radionuclide Theranostics via the ⁷⁰Zn(p,α)⁶⁷Cu Reaction

by Santiago Andrés Brühlmann, Martin Walther, Martin Kreller, Falco Reissig, Hans-Jürgen Pietzsch, Torsten Kniess and Klaus Kopka

Pharmaceuticals 2023, 16(2), 314; https://doi.org/10.3390/ph16020314 - 17 Feb 2023

Cited by 6 | Viewed by 2288

Abstract

Theranostic matched pairs of radionuclides have aroused interest during the last couple of years, and in that sense, copper is one element that has a lot to offer, and although ⁶¹Cu and ⁶⁴Cu are slowly being established as diagnostic radionuclides for [...] Read more.

Theranostic matched pairs of radionuclides have aroused interest during the last couple of years, and in that sense, copper is one element that has a lot to offer, and although ⁶¹Cu and ⁶⁴Cu are slowly being established as diagnostic radionuclides for PET, the availability of the therapeutic counterpart ⁶⁷Cu plays a key role for further radiopharmaceutical development in the future. Until now, the ⁶⁷Cu shortage has not been solved; however, different production routes are being explored. This project aims at the production of no-carrier-added ⁶⁷Cu with high radionuclidic purity with a medical 30MeV compact cyclotron via the ⁷⁰Zn(p,α)⁶⁷Cu reaction. With this purpose, proton irradiation of electrodeposited ⁷⁰Zn targets was performed followed by two-step radiochemical separation based on solid-phase extraction. Activities of up to 600MBq ⁶⁷Cu at end of bombardment, with radionuclidic purities over 99.5% and apparent molar activities of up to 80MBq/nmol, were quantified. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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Review

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22 pages, 6960 KiB

Open AccessReview

Lights and Shadows on the Sourcing of Silver Radioisotopes for Targeted Imaging and Therapy of Cancer: Production Routes and Separation Methods

by Marianna Tosato and Mattia Asti

Pharmaceuticals 2023, 16(7), 929; https://doi.org/10.3390/ph16070929 - 26 Jun 2023

Cited by 1 | Viewed by 1100

Abstract

The interest in silver radioisotopes of medical appeal (silver-103, silver-104m,g and silver-111) has been recently awakened by the versatile nature of their nuclear decays, which combine emissions potentially suitable for non-invasive imaging with emissions suited for cancer treatment. However, to trigger their in [...] Read more.

The interest in silver radioisotopes of medical appeal (silver-103, silver-104m,g and silver-111) has been recently awakened by the versatile nature of their nuclear decays, which combine emissions potentially suitable for non-invasive imaging with emissions suited for cancer treatment. However, to trigger their in vivo application, the production of silver radioisotopes in adequate amounts, and with high radionuclidic purity and molar activity, is a key prerequisite. This review examines the different production routes of silver-111, silver-103 and silver-104m,g providing a comprehensive critical overview of the separation and purification strategies developed so far. Aspects of quality (radiochemical, chemical and radionuclidic purity) are also emphasized and compared with the aim of pushing towards the future implementation of this theranostic triplet in preclinical and clinical contexts. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

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