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

GIP ARRONAXGIP ARRONAX

Radionuclide production for medical Applicationat the ARRONAX facility

Dr F. Haddad

SUBATECH and 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


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) : 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


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?


Molecular weight

Transittime

Full Antibody

Antibodyfragment

Low weight drug

Adapt T1/2 to the vector

Co

ncl

usi

on

s /

per

spec

tive

s

Zr-89 T1/2 = 78.4 hrI-124 T1/2 = 4.18 j …

Cu-64 T1/2 = 12.7 hr; Ga-68 T1/2 = 1.13 hr

Targeted therapy


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


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


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.


Beam Accelerated particles

Energy range (MeV)

Intensity (eµA)

Dual beam

Proton H- 30-70 <375 Yes

HH+ 17 <50 No

Deuteron D- 15-35 <50 Yes

Alpha He++ 68 <70 No

Main characteristics: Multi-particlesHigh energyHigh intensity


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


– 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 + ATSMImmuno–PET (64Cu, 89Zr, 76Br, …)

ARRONAX priority list


Rubidium-82 (82Rb): PET imaging in cardiology

Perfusion default

Bad corrections

Several advantages:Better corrections Quantification Shorter duration of the examLower dose to patient

99mTc-MIBI SPECT

82Rb-PETD. Le Guludec et al, Eur J Nucl Med Mol Imaging 2008; 35: 1709-24

82Sr/82Rb generator


natRb + p 82Sr + x

Low cross section

Energy range of interest

40 MeV-70 MeV

82Sr production

• Reaction and Cross section

Production needs high energy machines and high intensity beams


Our irradiation stations

Rabbit

ARRONAX irradiation station

Pressed pellet ofRbCl

Encapsulated RbCl

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


Extraction et separation du 82SrDissolution

Pastille RbCl irradi é e

Che

lex

100

82 Sr

82 Rb, 83 Rb, 83m Rb, 84 Rb, 86 Rb82 Sr, 85 Sr, 32 P, 83m Kr…

Rb, P, …

R é sine de s éparation

Purification de Sr

Irradiation dans un

Cyclotron de la

pastille de RbCl

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.

1,00E-04

2,00E+04

4,00E+04

6,00E+04

8,00E+04

1,00E+05

1,20E+05

1,40E+05

1,60E+05

0 50 100 150 200

V elution (mL)

Acti

vit

é (

Bq

)

Zone d'élution

Sr

Rb

Sr


Dismounting the rabbit

Processing in hot cells

Chemical separation

Dispensing


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) productions using deuteron beam have started for radiochemistry research.

•68Ge: The process for the target making (Ni/Ga alloy) is under completion


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


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

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.Barbet2,3

1 SUBATECH (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 Loirethe Université de Nantesthe 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.

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