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Radionuclide production for medical Application at the ARRONAX facility. Dr F. Haddad SUBATECH and GIP ARRONAX. Conquering Cancer: A Commitment For the Ones We Love. George Bush presidential library. Challenges:
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Radionuclide production for medical Applicationat the ARRONAX facility Dr F. HaddadSUBATECH and GIP ARRONAX
Conquering Cancer: A Commitment For the Ones We Love George Bush presidential library Challenges: • The genetics of cancer: how to betterpredictrisk and improveprevention? • How to detecttumorsearlierwhenthey are more easilycured • How to delivertargetedtreatmentat a cellular level, killing the cancer withoutharming patient • How to personalizetreatment to an individual’sspecific cancer profile • How viruses, antibodies, and otherbiologicalelementscanwork as microscopicweapons in the fightagainst cancer.
How to detecttumorsearlierwhenthey are more easilycured? • Radioactivity can be used • Penetrating radiation can be measured out of the body. • γ emitters (SPECT) : 99mTc, 201Tl , 111In, … • + emitter (PET) :18F, 11C, 15O, 82Rb, 68Ga,64Cu.. • Low penetrating radiation can be used for therapy: • - emitter:131I, 90Y, 177Lu, … • α emitter: 223Ra, 213Bi,211At,… • Augers emitter
Chelate Vector Etudes de cytotoxicité Cancer Cells How viruses, antibodies, and otherbiologicalelementscanwork as microscopicweapons in the fightagainstcancer? Targeted therapy
Adapt T1/2 to the vector Targetedtherapy Molecular weight Transit time Full Antibody Zr-89 T1/2 = 78.4 hr I-124 T1/2 = 4.18 j … Antibody fragment Conclusions / perspectives Cu-64 T1/2 = 12.7 hr; Ga-68 T1/2 = 1.13 hr Lowweightdrug
How to deliver targeted treatment at a cellular level, killing the cancer without harming patient? β emitter αemitter • <1 MeV dissipated over 1 to 10 mm • energy deposited outside the target cell • TARGET: • cell macro-clusters • metastases • 5-6 MeV dissipated over 0.1 mm • energy deposited within the target cells • TARGET: isolated cells, micro-clusters
How to personalize treatment to an individual’s specific cancer profile? • Conclusion: • There is a need for radionuclides with different • decay product • Half-lives • Chemical properties Theragnostics is a treatment strategy that combines therapeutics with diagnostics. Use of a pair of radionuclides(64Cu/67Cu, 124I/131I, …) to makedosimetrypriortherapy and see patient response
ARRONAX an Accelerator for Research in Radiochemistry and Oncology at Nantes Atlantique 3 main fields of investigations Radionuclides production for nuclear medicine (Oncology, Cardiology and Neurology) Associated research fields (Radiolysis, radiobiology and Nuclear Physics) Training linked to the university of Nantes and the school of mines.
Main characteristics: • Multi-particles • High energy • High intensity
P3 AX P2 A2 P1 A1 ARRONAX: the facility 4 Vaultsdevoted to isotope production and connected to hot cells through a pneumatic system Vault P1 devoted to a neutron activator system (collaboration with AAA company) Vault AX devoted to physics, radiolysis and radiobiologyexperiments
ARRONAX priority list • Radionuclide targeted therapy: 211At ( emitter) 67Cu, 47Sc(- emitters) • Dosimetry prior therapy : Radionulide pairs +/- :64/67Cu, 44/47Sc -Imaging : Cardiology:82Sr/82Rb Oncology:68Ge/68Ga Hypoxia : 64Cu + ATSM Immuno–PET (64Cu, 89Zr, 76Br,…)
Rubidium-82 (82Rb): PET imaging in cardiology Perfusion default D. Le Guludec et al, Eur J Nucl Med Mol Imaging 2008; 35: 1709-24 99mTc-MIBI SPECT 82Rb-PET Bad corrections • Several advantages: • Better corrections • Quantification • Shorter duration of the exam • Lower dose to patient 82Sr/82Rb generator
82Sr production Low cross section Energy range of interest 40 MeV-70 MeV natRb + p 82Sr + x • Reaction and Cross section Production needs high energy machines and high intensity beams
ARRONAX irradiation station Pressed pellet of RbCl Encapsulated RbCl Our irradiation stations Rabbit We have achieved 100µA on RbCl target for 100 h @ 70 MeV
Only few facilities are producing Sr-82 • LANL, USA –100 MeV, 200µA • BNL, USA –200 MeV, 100µA • INR, Russia –160 MeV, 120µA • iThemba, South Africa –66 MeV, 250µA • TRIUMF, Canada –110 MeV, 70 µA • ARRONAX, France – 70 MeV, 2*100µA BLIP
Irradiation dans un Dissolution Cyclotron de la 82 83 83m 84 86 Rb, Rb, Rb, Rb, Rb Pastille RbCl irradi é e 82 85 32 83m pastille de RbCl Sr, Sr, P, Kr … 85 Rb(p,4n) 82 Sr 100 Purification de Sr Chelex R é sine de s é paration Purification de Sr Sr Rb, P, … 82 Sr Rb Extraction and purification Extraction et separation du 82Sr Good separation Reproducibility verified Extraction yield = 92.9 % 3.7% (k=2) Purity of the product fulfills regulatory requirements.
Processing in hot cells Dismounting the rabbit Dispensing Chemical separation
Conclusions • ARRONAX is fully operational since February 2011. • ARRONAX priority list covers both isotopes for therapy (211At, 67Cu, 47Sc) and imaging (82Sr, 68Ge, 64Cu, 44Sc ) • 82Sr is produced routinely at 2*100µA at medical grade • 64Cu is produced at medical grade using deuteron beam. It is produced 2 times a month using tens of µA on target. • 211At production is linked to the use of a beam energy degrader with our alpha beam. • 44Sc :Regular small (~ mCi scale) productionsusing deuteron beam have started for radiochemistry research. • 68Ge: The process for the target making (Ni/Ga alloy) is under completion
Radiopharmaceutical: Setting up a network of expertise in Nantes Irradiations Biological targets Extraction and purification Vectors Radiolabelling Preclinical studies Radiopharmaceutical GMP Production Clinical trials Marketing
Conclusions • ARRONAX is also: • An experimental Hall Ax with • Radiolysis and radiobiology experiments with an 70MeV alpha beam • Cross section measurements using • the stacked foils technique • A High energy PIXE platform • An Hall P1 with • A neutron activator is installed for nanoparticles activation natTi(p,X)47Sc
Credit C. Alliot2,3, N. Audouin2, J. Barbet2,3, O. Batrak1, A.C. Bonraisin2, Y.Bortoli1, V.Bossé 2,3, C. Bourdeau2, G. Bouvet1, J.M. Buhour1, A. Cadiou1, S. Fresneau1, S. Girault2, M. Guillamet1, F. Haddad1,2, C. Huet2, J. Laizé2, E. Macé2,3, N.Michel1,2, T. Milleto1, M. Mokili1,2, L. Perrigaud2, C. Roustan2, N. Varmenot2, F. Poirier1,2, J.Barbet2,31SUBATECH (CNRS/IN2P3 - Ecole des mines - Université de Nantes) 2 GIP ARRONAX 3 Inserm U892,Nantes, France
Thank you for your attention • The ARRONAX project is supported by: • the Regional Council of Pays de la Loire • the Université de Nantes • the French government (CNRS, INSERM) • the European Union. • This work has been, in part, supported by a grant from the French National Agency for Research called "Investissements d'Avenir", Equipex Arronax-Plus noANR-11-EQPX-0004.