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CERN-MEDICIS robot isotope production for medical research

CERN-MEDical Isotopes Collected from ISOLDE (MEDICIS) is a facility located in the Isotope Separator Online DEvice (ISOLDE) facility at CERN, designed to produce high-purity isotopes for developing the practice of patient diagnosis and treatment. The facility was initiated in 2010, with its first radioisotopes (terbium-155) produced on 12 December 2017.[1]

The target used to produce radioactive nuclei at the ISOLDE facility only absorbs 10% of the proton beam.[2] MEDICIS positions a second target behind the first, which is irradiated by the leftover 90% of the proton beam. The target is then moved to an off-line mass separation system and isotopes are extracted from the target.[3] These isotopes are implanted in metallic foil and can be delivered to research facilities and hospitals.[4]

MEDICIS is a nuclear class A laboratory and takes into account various radioprotection procedures to prevent irradiation and contamination.[5]

Background

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An isotope of an element contains the same number of protons, but a different number of neutrons, giving it a different mass number than the element found on the periodic table. Isotopes with a large variation in nucleon number will decay into more stable nuclei, and are known as radionuclides or radioisotopes.

The field of nuclear medicine uses radioisotopes to diagnose and treat patients. The radiation and particles emitted by these radioisotopes can be used to weaken or destroy target cells, for example in the case of cancer. For diagnosis, a radioactive dose is given to a patient and its activity can be tracked to study the functionality of a target organ. The tracers used within this process are generally short-lived isotopes.[6]

Diagnostic radiopharmaceuticals are used to examine organ functionality, blood flow, bone growth and other diagnostic procedures.[citation needed] Radioisotopes needed for this procedure must emit gamma radiation with a high energy and short half-life, in order for it to escape the body and decay quickly.[7] There is currently a trend to use cyclotron-produced isotopes as they are becoming more widely available.[6]

Positron Emission of Fluorine-18

Positron emission tomography (PET) is an imaging technique, using radioisotopes also most often produced with a cyclotron.[8] They are injected into the patient, accumulating in the target tissue, and decays through positron emission. The positron annihilates with an electron nearby which results in the emission to two gamma rays (photons) in opposite directions. A PET camera detects these rays and can determine quantitative information about the target tissue.[9]

Therapeutic radiopharmaceuticals are used to destroy or weaken malfunctioning cells, using a radioisotope localised to a specific organ. This process is called radionuclide therapy (RNT), and uses heavy proton radioisotopes (located on the North-West area of the nuclide chart) that decay through beta or alpha emission.[10]

Facility and process

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MEDICIS announcement of initial construction in 2013

The MEDICIS facility is located in the extension of building 179 at the CERN Meyrin site, next to the ISOLDE building.[11] The facility was established by CERN in 2010, along with contributions from the CERN Knowledge Transfer Fund, as well as receiving a European Commission Marie-Skłodowska-Curie training grant under the title MEDICIS-PROMED.[12][13] The construction of the facility started in September 2013 and was completed in 2017.[14][3]

ISOLDE directs a 1.4 GeV proton beam from the Proton Synchrotron Booster (PSB) onto a thick target, the material dependent on the desired produced isotopes. Only 10% of the proton beam used in the ISOLDE facility is absorbed by the target, with the rest otherwise hitting the beam dump.[15] MEDICIS uses these wasted protons to irradiate a second target, which produces specific isotopes, placed behind each of ISOLDE's target stations, the High Resolution Separator (HRS) and the General Purpose Separator (GPS).[3] Alternatively, the facility uses pre-irradiated targets that are provided by external institutions.[16] MEDICIS was one of the few facilities operating throughout the Long Shutdown 2, due to it being provided with 34 externally irradiated target materials.[3]

MEDICIS Promed training with Nobel prize winner, Kostya Novozelov

Due to the high levels of radiation, the targets are transferred from the irradiation station to the radioisotope mass-separation beamline using an automated rail conveyer system (RCS).[1][3] A KUKA robot is used to transport the target to the station, where the isotope of interest can be collected and radiochemically purified.[17] This is done by heating the target up to very high temperatures, often more than 2000 °C, which causes the specified isotopes to diffuse. The isotopes are then ionised and accelerated by an ion source to be sent through a mass separator. The mass separator extracts the isotope of interest so that it can be implanted onto thin gold foils with a one-sided metallic or salt coating.[18][19]

In 2019, the MEDICIS Laser Ion Source Setup At CERN (MELISSA) became fully operational, containing the individual lasers, auxiliary and control systems, and optical beam transport.[20] The MELISSA laser laboratory has helped to successfully increase the separation efficiency and the yield of the isotopes.[16][3] The laser excites only isotopes of the desired element, allowing an element-selective isotope separation for a given atomic mass from other isobars by the mass separator.[21]

A shielded trolley is used to retrieve the samples after the radioisotopes have been collected, in order to avoid risk of contamination.[19] Once the target is finished being used, it is sent to a hot cell in order to be safely dismantled and put in waste bins.

Glovebox at the nanolaboratory at MEDICIS

Once collected, the samples can be sent to hospitals and research facilities with the purpose of developing patient imaging and treatment, and therapy protocols.[22]

Additionally next to the MEDICIS facility, there is a nanolab laboratory designed for the development and assembly of nanomaterials.[23] The nanomaterials are sealed in a glovebox, meaning there is no contact with the outside environment.[24] It builds up on the development of the first nanostructured targets used for isotope production, and further exploits developments initiated in MEDICIS-Promed under the guidance of Prof. "Kostya" Novozelov.

Projects and results

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Targeted therapy

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Several lanthanides produced at CERN-MEDICIS, samarium and terbium, are of interest for targeted therapy alike lutetium already used in the clinics.[25] Lutetium emits low energy β particles with a short range, used for irradiation of smaller volume tumor targets.[26] Terbium-149 emits short-range alpha particles, gamma-rays and positrons, in its decay scheme, which makes it suitable for targeted alpha therapy. The particular study of 149Tb produced by ISOLDE has been in folate receptor therapy, prominent in ovarian and lung cancer.[25][27]

153Sm, produced in the BR2 reactor at SCK CEN, followed by the subsequent mass separation by MEDICIS to increase its molar activity, was found to be suitable for targeted radionuclide therapy (TRNT) in a proof-of-concept research project.[28] It emits low energy β particles and gamma peaks, and presents acceptable half-life for logistics and ambulatory care, making it a candidate of choice for theranostics approaches.

Theranostics

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SPECT-CT images at (a) 4h post injection and (b) 24h post injection

Theranostics, a treatment that combines therapy and diagnosis, is a new trend in precision medicine where the radioisotopes produced at MEDICIS already triggered research projects. The strategy the facility uses is to find an element that has two radioisotopes, used for imaging and therapy separately.[29]

A promising element for use in theranostics is terbium as it has four different radioisotopes for use in therapy and PET or SPECT imaging. In 2021, Tb radioisotope production was successfully performed with the MELISSA laser ion source, with a 53% ionisation efficiency obtained by MEDICIS-Promed students.[30] Since 2021, three other non-conventional isotopes of interest for PET imaging or therapeutic applications have been produced.[31]

Exploration of mass separated 153Sm at MEDICIS using in vitro biological studies showed that the ability for tumors to absorb (uptake) and retain substances (retention) was improved compared to normal tissues. Animal SPECT-CT scans of mice were obtained post-injection and showed cleared activity after twenty-four hours.[32]

Involvement with PRISMAP

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The PRoduction of high purity Isotopes by mass Separation for Medical APplication (PRISMAP) is the European medical radionuclide programme, with the goal to provide a sustainable source of high-purity radioisotopes for medicine.[33][34] The programme brings together 23 beneficiaries from 13 countries, to create a single entry point for the medical isotope user community.[35] The MEDICIS facility provides mass separation of isotopes, which can then be transported to nearby research facilities hosting external researchers to limit long haul transport of the samples.[36]

References

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  1. ^ a b "MEDICIS shows its strength". CERN Courier. 2020-12-18. Retrieved 2023-07-10.
  2. ^ "CERN-MEDICIS produces first medical isotopes". Physics World. 2017-12-13. Retrieved 2023-07-10.
  3. ^ a b c d e f Duchemin, Charlotte; Ramos, Joao P.; Stora, Thierry; Ahmed, Essraa; Aubert, Elodie; Audouin, Nadia; Barbero, Ermanno; Barozier, Vincent; Bernardes, Ana-Paula; Bertreix, Philippe; Boscher, Aurore; Bruchertseifer, Frank; Catherall, Richard; Chevallay, Eric; Christodoulou, Pinelopi (2021). "CERN-MEDICIS: A Review Since Commissioning in 2017". Frontiers in Medicine. 8: 693682. doi:10.3389/fmed.2021.693682. PMC 8319400. PMID 34336898.
  4. ^ Pixels 2, Rockin (2018-01-02). "The new CERN facility can contribute towards cancer research". Foro Nuclear. Retrieved 2023-07-11.{{cite web}}: CS1 maint: numeric names: authors list (link)
  5. ^ Bernardes, A P (15 Oct 2014). "Integrating Safety into MEDICIS project" (PDF). Retrieved 24 July 2023.
  6. ^ a b "Radioisotopes in Medicine | Nuclear Medicine - World Nuclear Association". www.world-nuclear.org. Retrieved 2023-07-17.
  7. ^ Drozdovitch, Vladimir; Brill, Aaron B.; Callahan, Ronald J.; Clanton, Jeffrey A.; DePietro, Allegra; Goldsmith, Stanley J.; Greenspan, Bennett S.; Gross, Milton D.; Hays, Marguerite T.; Moore, Stephen C.; Ponto, James A.; Shreeve, Walton W.; Melo, Dunstana R.; Linet, Martha S.; Simon, Steven L. (May 2015). "Use of Radiopharmaceuticals in Diagnostic Nuclear Medicine in the United States: 1960–2010". Health Physics. 108 (5): 520–537. doi:10.1097/HP.0000000000000261. ISSN 0017-9078. PMC 4376015. PMID 25811150.
  8. ^ "PET Cyclotron and Radiopharmacy Facility". www.bccancer.bc.ca. Retrieved 2023-07-17.
  9. ^ Ollinger, J.M.; Fessler, J.A. (Jan 1997). "Positron-emission tomography". IEEE Signal Processing Magazine. 14 (1): 43–55. Bibcode:1997ISPM...14...43O. doi:10.1109/79.560323. hdl:2027.42/85853.
  10. ^ Hosono, Makoto (1 June 2019). "Perspectives for Concepts of Individualized Radionuclide Therapy, Molecular Radiotherapy, and Theranostic Approaches". Nuclear Medicine and Molecular Imaging. 53 (3): 167–171. doi:10.1007/s13139-019-00586-x. ISSN 1869-3482. PMC 6554368. PMID 31231436.
  11. ^ "The building | CERN-MEDICIS". medicis.cern. Retrieved 2023-07-11.
  12. ^ "CERN-MEDICIS: Novel Isotopes for Medical Research | Knowledge Transfer". kt.cern. Retrieved 2023-07-11.
  13. ^ European Commission (2015-04-01). "MEDICIS-produced radioisotope beams for medicine". Horizon 2020. doi:10.3030/642889.
  14. ^ Lo, Chris (2017-10-20). "CERN-MEDICIS: backing nuclear medicine". Pharmaceutical Technology. Retrieved 2023-07-11.
  15. ^ Brown, Alexander (1 September 2015). Design of the CERN MEDICIS Collection and Sample Extraction System. University of Manchester (Thesis).
  16. ^ a b Gadelshin, V. M.; Barozier, V.; Cocolios, T. E.; Fedosseev, V. N.; Formento-Cavaier, R.; Haddad, F.; Marsh, B.; Marzari, S.; Rothe, S.; Stora, T.; Studer, D.; Weber, F.; Wendt, K. (2020-01-15). "MELISSA: Laser ion source setup at CERN-MEDICIS facility. Blueprint". Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 463: 460–463. Bibcode:2020NIMPB.463..460G. doi:10.1016/j.nimb.2019.04.024. ISSN 0168-583X. S2CID 182312164.
  17. ^ MEDICIS. "Making new medical radionuclides available for cancer research" (PDF). Indico. Retrieved 11 July 2023.
  18. ^ Duchemin, Charlotte; Barbero-Soto, Esther; Bernardes, Ana; Catherall, Richard; Chevallay, Eric; Cocolios, Thomas; Dorsival, Alexandre; Fedosseev, Valentin; Fernier, Pascal; Gilardoni, Simone; Grenard, Jean-Louis; Haddad, Ferid; Heinke, Reinhard; Khan, Muhammad Asif; Lambert, Laura (2020). "CERN-MEDICIS: A Unique Facility for the Production of Non-Conventional Radionuclides for the Medical Research". Proceedings of the 11th International Particle Accelerator Conference. IPAC2020. Seidel Mike (Ed.), Aßmann, Ralph W. (Ed.), Chautard Frédéric (Ed.), Schaa, Volker R.W. (Ed.): 5 pages, 0.595 MB. doi:10.18429/JACOW-IPAC2020-THVIR13. ISSN 2673-5490.
  19. ^ a b "The MEDICIS laboratory | CERN-MEDICIS". medicis.cern. Retrieved 2023-07-11.
  20. ^ "The MELISSA laboratory | CERN-MEDICIS". medicis.cern. Retrieved 2023-07-13.
  21. ^ Gadelshin, Vadim Maratovich; Wilkins, Shane; Fedosseev, Valentin Nikolaevich; Barbero, Ermanno; Barozier, Vincent; Bernardes, Ana-Paula; Chevallay, Eric; Cocolios, Thomas Elias; Crepieux, Bernard; Dockx, Kristof; Eck, Matthias; Fernier, Pascale; Cavaier, Roberto Formento; Haddad, Ferid; Jakobi, Johannes (2020-05-06). "First laser ions at the CERN-MEDICIS facility". Hyperfine Interactions. 241 (1): 55. Bibcode:2020HyInt.241...55G. doi:10.1007/s10751-020-01718-y. hdl:10995/90409. ISSN 1572-9540. S2CID 254553308.
  22. ^ Schopper, Herwig; Lella, Luigi Di (2015-07-13). 60 Years Of Cern Experiments And Discoveries. World Scientific. ISBN 978-981-4644-16-7.
  23. ^ "Radioactive Beam Sources (RBS) | Sources, Targets and Interactions Group (STI)". sy-dep-sti.web.cern.ch. Retrieved 2023-08-14.
  24. ^ "79th ISCC meeting | ISOLDE". isolde.cern. Retrieved 2023-08-14.
  25. ^ a b Burkhardt, Claudia; Bühler, Léo; Viertl, David; Stora, Thierry (2021-08-02). "New Isotopes for the Treatment of Pancreatic Cancer in Collaboration With CERN: A Mini Review". Frontiers in Medicine. 8: 674656. doi:10.3389/fmed.2021.674656. ISSN 2296-858X. PMC 8365147. PMID 34409048.
  26. ^ Fonslet, Jasper (2017). "Production and utilization of unconventional radiometals for advanced diagnostics and therapy" (PDF). DTU Nutech.
  27. ^ Müller, Cristina; Reber, Josefine; Haller, Stephanie; Dorrer, Holger; Köster, Ulli; Johnston, Karl; Zhernosekov, Konstantin; Türler, Andreas; Schibli, Roger (2014-03-13). "Folate Receptor Targeted Alpha-Therapy Using Terbium-149". Pharmaceuticals. 7 (3): 353–365. doi:10.3390/ph7030353. ISSN 1424-8247. PMC 3978496. PMID 24633429.
  28. ^ Stora, Thierry; Prior, John O.; Decristoforo, Clemens (2022-10-03). "Editorial: MEDICIS-promed: Advances in radioactive ion beams for nuclear medicine". Frontiers in Medicine. 9. doi:10.3389/fmed.2022.1013619. ISSN 2296-858X. PMC 9574352. PMID 36262271.
  29. ^ Cavaier, R. Formento; Haddad, F.; Sounalet, T.; Stora, T.; Zahi, I. (2017-01-01). "Terbium Radionuclides for Theranostics Applications: A Focus On MEDICIS-PROMED". Physics Procedia. Conference on the Application of Accelerators in Research and Industry, CAARI 2016, 30 October – 4 November 2016, Ft. Worth, TX, USA. 90: 157–163. Bibcode:2017PhPro..90..157C. doi:10.1016/j.phpro.2017.09.053. ISSN 1875-3892.
  30. ^ Gadelshin, Vadim Maratovich; Formento Cavaier, Roberto; Haddad, Ferid; Heinke, Reinhard; Stora, Thierry; Studer, Dominik; Weber, Felix; Wendt, Klaus (2021). "Terbium Medical Radioisotope Production: Laser Resonance Ionization Scheme Development". Frontiers in Medicine. 8: 727557. doi:10.3389/fmed.2021.727557. PMC 8546115. PMID 34712678.
  31. ^ Bernerd, C.; Johnson, J. D.; Aubert, E.; Au, M.; Barozier, V.; Bernardes, A. -P.; Bertreix, P.; Bruchertseifer, F.; Catherall, R.; Chevallay, E.; Chrysalidis, K.; Christodoulou, P.; Cocolios, T. E.; Crepieux, B.; Deschamps, M. (2023-09-01). "Production of innovative radionuclides for medical applications at the CERN-MEDICIS facility". Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 542: 137–143. Bibcode:2023NIMPB.542..137B. doi:10.1016/j.nimb.2023.05.008. ISSN 0168-583X. S2CID 259717417.
  32. ^ Vermeulen, Koen; Van de Voorde, Michiel; Segers, Charlotte; Coolkens, Amelie; Rodriguez Pérez, Sunay; Daems, Noami; Duchemin, Charlotte; Crabbé, Melissa; Opsomer, Tomas; Saldarriaga Vargas, Clarita; Heinke, Reinhard; Lambert, Laura; Bernerd, Cyril; Burgoyne, Andrew R.; Cocolios, Thomas Elias (Dec 2022). "Exploring the Potential of High-Molar-Activity Samarium-153 for Targeted Radionuclide Therapy with [153Sm]Sm-DOTA-TATE". Pharmaceutics. 14 (12): 2566. doi:10.3390/pharmaceutics14122566. ISSN 1999-4923. PMC 9785812. PMID 36559060.
  33. ^ MEDICIS. "PRISMAP The European medical isotope programme" (PDF). medicis.cern. Retrieved 12 July 2023.
  34. ^ "Project description". PRISMAP. Retrieved 2023-07-12.
  35. ^ "PRISMAP Call for Projects". EANM. 2021-12-17. Retrieved 2023-07-12.
  36. ^ "PRISMAP – The European medical radionuclides programme sets out to transform the European landscape for novel and emerging medical radionuclides - ILL Neutrons for Society". www.ill.eu. Retrieved 2023-07-12.
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