Radionuclide production for medical Application
at the ARRONAX facility
Dr F. Haddad
SUBATECH and GIP ARRONAX
GIP ARRONAX
Conquering Cancer:
A Commitment For the
Ones We Love
George Bush presidential library
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.
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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
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How viruses, antibodies, and other biological
elements can work as microscopic weapons in the
fight against cancer?
Targeted therapy
Vector
Chelate
Etudes de
cytotoxicité
Cancer Cells
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Targeted therapy
Conclusions / perspectives
Molecular
weight
Transit
time
Full Antibody
Adapt T1/2 to the vector
Zr-89 T1/2 = 78.4 hr
I-124 T1/2 = 4.18 j …
Antibody
fragment
Low weight drug
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Cu-64 T1/2 = 12.7 hr;
Ga-68 T1/2 = 1.13 hr
How to deliver targeted treatment at a cellular
level, killing the cancer without harming patient?
β emitter
α emitter
• <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, microclusters
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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
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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.
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Main characteristics:
Multi-particles
High energy
High intensity
Beam
Proton
Accelerated
Energy
particles
range (MeV)
Intensity
(eµA)
Dual
beam
H-
30-70
<375
Yes
HH+
17
<50
No
Deuteron
D-
15-35
<50
Yes
Alpha
He++
68
<70
No
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ARRONAX: the facility
4 Vaults devoted to isotope production
and connected to hot cells through a
pneumatic system
P3
P2
AX
A2
P1
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A1
Vault P1 devoted to a neutron activator
system (collaboration with AAA company)
Vault AX devoted to physics, radiolysis
and radiobiology experiments
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, …)
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Rubidium-82 (82Rb): PET imaging in cardiology
Perfusion default
99mTc-MIBI
82Rb-PET
SPECT
D. Le Guludec et al, Eur J
Nucl Med Mol Imaging
2008; 35: 1709-24
Bad corrections
Several advantages:
Better corrections
Quantification
Shorter duration of the exam
Lower dose to patient
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82Sr/82Rb
generator
82Sr
• Reaction and Cross section
production
natRb
+ p  82Sr + x
Low cross section
Energy range of
interest
40 MeV-70 MeV
Production needs high energy machines and high intensity beams
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ARRONAX irradiation station
Our irradiation stations
Pressed pellet of
RbCl
Encapsulated
RbCl
Rabbit
We have achieved 100µA on RbCl target for 100 h @ 70 MeV
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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
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BLIP
Extraction and purification
Extraction et separation du 82Sr
Irradiation dans un
Dissolution
pastille de
85
Rb(p,4n)
RbCl
82
82
Rb, 83 Rb, 83m Rb, 84 Rb,
82
85
32
83m
Sr, Sr, P,
Kr…
Pastille RbCl irradi é e
Sr
R é sine de s é paration
Chelex 100
Cyclotron de la
86
Rb
Purification de Sr
Purification de Sr
82
Sr
1,60E+05
Rb, P, …
Zone
d'élution
Sr
1,40E+05
Sr
Activité (Bq)
1,20E+05
1,00E+05
Rb
8,00E+04
Good separation
6,00E+04
Reproducibility verified
4,00E+04
Extraction yield = 92.9 %  3.7% (k=2)
2,00E+04
1,00E-04
0
50
100
150
V elution (mL)
Purity of the product fulfills regulatory requirements.
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200
Processing in hot cells
Dismounting the rabbit
Chemical separation
Dispensing
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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
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Radiopharmaceutical:
Setting up a network of expertise in Nantes
Irradiations
Biological targets
Extraction and
purification
Vectors
Radiolabelling
Preclinical studies
Radiopharmaceutical
GMP Production
Clinical trials
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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
natTi(p,X)47Sc
A High energy PIXE platform
An Hall P1 with
A neutron activator is installed for nanoparticles activation
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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
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.
GIP ARRONAX