1. GIP ARRONAX Radionuclide production for medical Application at the ARRONAX facility Dr F. Haddad SUBATECH and GIP ARRONAX

2. GIP ARRONAX Challenges: The genetics of cancer: how to better predict risk and improve prevention? How to detect tumors earlier when they are more easily cured How to deliver targeted treatment at a cellular level, killing the cancer without harming patient How to personalize treatment to an individual’s specific cancer profile How viruses, antibodies, and other biological elements can work as microscopic weapons in the fight against cancer. Conquering Cancer: A Commitment For the Ones We Love George Bush presidential library

3. GIP ARRONAX How to detect tumors earlier when they are more easily cured? Radioactivity can be used Penetrating radiation can be measured out of the body. γ emitters (SPECT) : 99m Tc, 201 Tl, 111 In, …  + emitter (PET) : 18 F, 11 C, 15 O, 82 Rb, 68 Ga, 64 Cu.. Low penetrating radiation can be used for therapy:  - emitter: 131 I, 90 Y, 177 Lu, … α emitter: 223 Ra, 213 Bi, 211 At,… Augers emitter

4. GIP ARRONAX Vector Chelate Cancer Cells Etudes de cytotoxicité Targeted therapy How viruses, antibodies, and other biological elements can work as microscopic weapons in the fight against cancer?

5. GIP ARRONAX Molecular weight Transit time Full Antibody Antibody fragment Low weight drug Adapt T 1/2 to the vector Conclusions / perspectives Zr-89 T 1/2 = 78.4 hr I-124 T 1/2 = 4.18 j … Cu-64 T 1/2 = 12.7 hr; Ga-68 T 1/2 = 1.13 hr Targeted therapy

6. GIP ARRONAX How to deliver targeted treatment at a cellular level, killing the cancer without harming patient? β emitter <1 MeV dissipated over 1 to 10 mm energy deposited outside the target cell TARGET: cell macro-clusters metastases α emitter 5-6 MeV dissipated over 0.1 mm energy deposited within the target cells TARGET: isolated cells, micro- clusters

7. GIP ARRONAX How to personalize treatment to an individual’s specific cancer profile? Theragnostics is a treatment strategy that combines therapeutics with diagnostics.  Use of a pair of radionuclides (64Cu/67Cu, 124I/131I, …) to make dosimetry prior therapy and see patient response Conclusion: There is a need for radionuclides with different –decay product –Half-lives –Chemical properties

8. GIP ARRONAX an Accelerator for Research in Radiochemistry and Oncology at Nantes Atlantique ARRONAX 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.

9. GIP ARRONAX BeamAccelerated particles Energy range (MeV) Intensity (eµA) Dual beam ProtonH-30-70<375Yes HH+17<50No DeuteronD-15-35<50Yes AlphaHe++68<70No Main characteristics: Multi-particles High energy High intensity

10. GIP ARRONAX ARRONAX: the facility P3 P2 P1 AX A2 A1 4 Vaults devoted 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 radiobiology experiments

11. GIP ARRONAX –Radionuclide targeted therapy: 211 At (  emitter) 67 Cu, 47 Sc (  - emitters) –Dosimetry prior therapy : Radionulide pairs  + /  - : 64/67 Cu, 44/47 Sc - Imaging : Cardiology: 82 Sr/ 82 Rb Oncology: 68 Ge/ 68 Ga Hypoxia : 64 Cu + ATSM Immuno–PET ( 64 Cu, 89 Zr, 76 Br, …) ARRONAX priority list

12. GIP ARRONAX Rubidium-82 (82Rb): PET imaging in cardiology Perfusion default Bad corrections Several advantages: Better corrections Quantification Shorter duration of the exam Lower dose to patient 99m Tc-MIBI SPECT 82 Rb-PET D. Le Guludec et al, Eur J Nucl Med Mol Imaging 2008; 35: 1709-24 82 Sr/ 82 Rb generator

13. GIP ARRONAX nat Rb + p  82 Sr + x Low cross section Energy range of interest 40 MeV-70 MeV 82 Sr production Reaction and Cross section Production needs high energy machines and high intensity beams

14. GIP ARRONAX Our irradiation stations Rabbit ARRONAX irradiation station Pressed pellet of RbCl Encapsulated RbCl We have achieved 100µA on RbCl target for 100 h @ 70 MeV

15. GIP ARRONAX 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

16. GIP ARRONAX Extraction et separation du 82 Sr Dissolution PastilleRbClirradiée Chelex 100 82 Sr 82 Rb, 83 Rb, 83m Rb, 84 Rb, 86 Rb 82 Sr, 85 Sr, 32 P, 83m Kr… Rb, P,… Résine de séparation Purification de Sr Irradiation dans un Cyclotron de la pastille deRbCl 85 Rb(p,4n) 82 Sr Purification de Sr Good separation Reproducibility verified Extraction yield = 92.9 %  3.7% (k=2) Extraction and purification Purity of the product fulfills regulatory requirements. Rb Sr

17. GIP ARRONAX Dismounting the rabbit Processing in hot cells Chemical separation Dispensing

18. GIP ARRONAX Conclusions ARRONAX is fully operational since February 2011. ARRONAX priority list covers both isotopes for therapy ( 211 At, 67 Cu, 47 Sc) and imaging ( 82 Sr, 68 Ge, 64 Cu, 44 Sc ) 82 Sr is produced routinely at 2*100µA at medical grade 64 Cu is produced at medical grade using deuteron beam. It is produced 2 times a month using tens of µA on target. 211 At production is linked to the use of a beam energy degrader with our alpha beam. 44 Sc : Regular small (~ mCi scale) productions using deuteron beam have started for radiochemistry research. 68 Ge: The process for the target making (Ni/Ga alloy) is under completion

19. GIP ARRONAX Irradiations Extraction and purification Radiolabelling Biological targets Vectors Radiopharmaceutical Preclinical studies Clinical trials Marketing GMP Production Radiopharmaceutical: Setting up a network of expertise in Nantes

20. GIP ARRONAX 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 Conclusions nat Ti(p,X) 47 Sc

21. GIP ARRONAX Credit C. Alliot 2,3, N. Audouin 2, J. Barbet 2,3, O. Batrak 1, A.C. Bonraisin 2, Y.Bortoli 1, V.Bossé 2,3, C. Bourdeau 2, G. Bouvet 1, J.M. Buhour 1, A. Cadiou 1, S. Fresneau 1, S. Girault 2, M. Guillamet 1, F. Haddad 1,2, C. Huet 2, J. Laizé 2, E. Macé 2,3, N.Michel 1,2, T. Milleto 1, M. Mokili 1,2, L. Perrigaud 2, C. Roustan 2, N. Varmenot 2, F. Poirier 1,2, J.Barbet 2,3 1 SUBATECH (CNRS/IN2P3 - Ecole des mines - Université de Nantes) 2 GIP ARRONAX 3 Inserm U892,Nantes, France

22. GIP ARRONAX 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.