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Multifunctional gold nanoparticles
for image-guided radiotherapy
Gautier Laurent1, Christophe Alric2, Claire Bernhard3, Sandrine Dufort4, FrédéricBoschetti5, Valerie Bentivegna6, Nirmitha Herath7, Rana Bazzi1, François Lux2, Marie Boschetti5, Valerie Bentivegna6, Nirmitha Herath7, Rana Bazzi1, François Lux2, Marie
Dutreix7, Pascal Perriat8, Franck Denat3, Géraldine Le Duc6, Olivier Tillement2, Stéphane Roux 1
1 Institut UTINAM, Université de Franche-Comté, France.2 LPCML, Université Claude Bernard Lyon1, France.
3 ICMUB, Université de Bourgogne, France, 4 Nano-H SAS, France.
5 CheMatech SAS, France. 6 ID17 Biomedical Beamline, ESRF, France.
7 Institut Curie, France. 8 MATEIS, INSA Lyon, France
The limitations of the conventional radiotherapy
Tumor Healthy tissue
D1
X-rays
Conventional
Radiation therapy
Low difference between tumor
and healthy tissue irradiation
Not sufficiently selective
The radiosensitization: a strategy for overcoming the limitations
Healthy tissueTumor
D2<D1
X-rays
Tumor loaded with
radiosensitizing agents
Radiations are focussed in tumor
and healthy tissues are spared
A prefential targeting of the tumor is required
Why are the nanoparticles better suited for tumor targeting?
Endothelial cell
Passive
targeting
Tumor cell
Leaky vasculature of tumor
Normal cell
TumorHealthy tissue
Tight jonction
Blood vessel
Active targeting
Leaky vasculature of tumor
Stealth nanoparticleNanoparticle with
targeting moleculeSmall molecule
Molecule overexpressed
by tumor cells
Preferential accumulation of the nanoparticles in the tumor
Principle of the image-guided therapy
Isignal(t)
t
tumour
Healthy tissue
Irradiation
Physical stimulus
(X or , magnetic field, NIR light)
Nanoparticles combining
medical imaging and
remotely controlled therapy
(X or γ-ray, magnetic field, NIR light)
Tumour
Treatment limited to the tumour
Sparing of healthy tissue
Improvement of the
therapeutic activity: ☺
Intravenous Injection of
nanoparticles
In vivo imaging
Why gold nanoparticles?
Localized surface plasmonresonance
Tunable optical
Strong X-ray photons absorption (high Z)
Au ?
RadiotherapyCT imaging
Tunable opticalproperties
Facile functionalization
Additional complementary properties: control of the biodistribution, imaging multimodality
Well suited for image-guided radiotherapy
Photothermaltherapy
Synthesis and characterisation of Au@DTDTPA nanoparticles
Au
� Synthesis
DTDTPA
10
15
20
25
Core size : ~2.4 nm
7
10 g.L–1 0,1 g.L–1
M+
Au
� entrapment of cationic species in the DTDTPA shell)
� Additionnal properties owing to the
formation of metal ion chelates
AdvFunctMater 2006, JACS 2008, Radiology 2011, Nanoscale 2013
0
5
10
1 10 100
~ 2,4 nm ~ 6,6 nm
DTDTPA
Au
Labelling of implants for diabetes I by Au@DTDTPA-Gd nanoparticles
� In vitro and in vivo detection and in vivo evaluation of labelled implants
Au
Au
IRM T1 IRM T2* Imagerie X Ultrasons IRM T1 Imagerie X
Au Au
T1-MRI T2*-MRI CT US T1-MRI CT
8
AuAu
Ultrasons- β cells (production of insuline)
(�) healthy mice
(�) non-treated diabetic mice
(�) diabetic mice treated by
labelled microcapsules
Limite diabète
Au
Au
Au
AuAu
Au
- Au@DTDTPA-Gd50 nanoparticles
Microcapsules of alginate APSA+GG :
Implantation in the abdomen
(~ 6000 microcapsules)
Days
[Glu
cose
] sa
ng
(m
g.d
L–1)
US
Radiology 2011
Radiosensitizing effect of Au@DTDTPA nanoparticles
40
50
60
70
80 Unlabeled U87 cells Au@DTDTPA-Gd
50 labeled U87 cells
Au@DTDTPA labeled U87 cellsM
ean
tail
mom
ent (
a. u
.)
9
No irradiation 5 Gy 10 Gy0
10
20
30
Mea
n ta
il m
omen
t (a.
u.)
Me
an
ta
il m
om
en
t /a
.u.
Efficient radiosensitizerMTM (unlabelled cells 10 Gy) = MTM (labelled cells 5 Gy )
Radiosensitizing effect of Au@DTDTPA nanoparticles
D0
Au@DTDTPA
+
MRT
Implantation Irradiation Sacrifice
D11 D61
� Microbeam Radiation Therapy (MRT, CF 400Gy, 50 µm, ctc 200 µm)
�Intratumoral injection | Rat bearing osteosarcoma
10
MRT
Au@DTDTPA
Control
0 5 10 15 20 25 30 35 40 45 50 55 60 65
Delay after implantation (days)Delay after implantation /day
Small 2014MRT + AuDTDTPA : higher MeST
Biodistribution study of Au@DTDTPA
� in vivo MRI of healthy mice
KIDNEYS
t0-5 t0+15 t0+30 t0+45
t0: intravenous injection of Au@DTDTPA-Gd50
([Au] = 10 g.L-1)75 µmol Gd / kg
t > t
11JACS 08
BLADDER
t0-5 t0+15 t0+30 t0+45
t > t0Positive contrast
enhancement
1°) kidneys2°) bladder
Biodistribution study of Au@DTDTPA
� in vivo planar γ scintigraphy of healthy rats
Au99mTc ; 111In
Au
111In111In
Au@DTDTPA-99mTcAu@DTDTPA-99mTc Au@DTDTPA-111In
t0 + 20 min t0 + 24 h
Au@DTDTPA-99mTc
Au@DTDTPA-111In
Intravenous
injection
t0
t0 + 72 h
12
t0 + 30 min
No undesirable accumulation in the organs
renal clearance
Nanoscale 2013
100 MBq 5 - 45 MBq
Biodistribution study of Au@DTDTPA
� gamma counting and determination of gold content in the organs as a
function of time (intravenous injection to healthy animals)
15
50
60
Fra
ctio
n de
la d
ose
d'or
inje
ctée
(%
)
30 min 24 h 48 h 72 h
15
60
70
inje
ctée
(%
)
30 min 24 h 48 h 72 h
Au
ICP analysis
Au
Gamma counting
13
Cerve
auCad
avre
Cœur
Foie
Muscle Os
Peau
Poumon
s
Rate
Reins
Intes
tinSan
g
0
5
10
Fra
ctio
n de
la d
ose
d'or
inje
ctée
(%
)
Cerve
auCad
avre
Cœur
FoieMus
cle OsPea
uPou
mons
Rate
Reins
Intes
tinSan
g
0
5
10
15
Aor
gane
/Ain
ject
ée
� Strong correlation between gamma counting and ICP analysis
���� no leakage of indium-111
� Renal clearance and absence of undesirable accumulation
Renal clearance of Au@DTDTPA-M
30
40
50
60
70
80
Cum
ulat
ive
% In
ject
ed d
ose
Feces Urine
14
30min 24h 48h 72h0
10
20
30
Cum
ulat
ive
% In
ject
ed d
ose
Time after injection
Removal of the nanoparticles essentially by renal excretion
� Intravenous injection | Rat bearing brain tumor (gliosarcoma 9L)
Injection of
Au@DTDTPA-Gd50
[Au] ~ 50 mM
[Gd] ~ 5 mM
Vinj = 1,4 mL
Biodistribution study of Au@DTDTPA-Gd50
9500
10000
10500
11000
11500
12000 Tumor Healthy tissue
Sig
nal i
nten
sity
(a.
u.)
a)
t0 – 2 min
b)
c)
15
Vinj = 1,4 mL
T1-weighted MRI 7T
The most opportune moment for
inducing radiotherapy
0 5 10 15 20 25 308000
8500
9000
9500
Sig
nal i
nten
sity
(a.
u.)
Time (minutes)
b)
t0 + 5 min
Radiosensitizing effect of Au@DTDTPA nanoparticles
50
60
70
80
90
100
Sur
viva
l (%
)
� Microbeam Radiation Therapy (MRT , CF 400Gy, 50 µm, ctc 200 µm)
�Intravenous injection | Rat bearing brain tumor (gliosarcoma 9L)
16
0
10
20
30
40
50
0 50 100 150 200 250 300 350
Sur
viva
l (%
)
Days after the implantation of the tumor
NT
MRT MRT 5’pi
Small 2014
Conclusion
� high colloidal stability in biological conditions
� free circulation in blood pool without undesirable
t0+30 min
RK
U
Au@L-(Gd, In, Tc)
17High potential for image-guidedradiotherapy
pool without undesirable non-specific accumulation
� Renal clearance
� Medical imaging (CT, MRI, scintigraphy)
� Radiosensitzing effect
t0 + 30 min
AdvFunctMater 2006, JACS 2008, Radiology 2011, Nanoscale 2013, Small 2014
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200
surv
iva
nts
(%
)
jours après l'implantation
MRT 5’ pi
MRTNT
4 min after IV injectionof of Au@DTDTPA-Gd
Acknowledgements
Gautier LaurentRana Bazzi
Olivier TillementFrançois LuxLucie SanceyCharles TruilletChristophe Alric
Géraldine Le DucElke Bräuer-KrischHerwig Requardt
Pascal Perriat
Christophe Alric
Franck Denat, Claire Bernhard
Marie DutreixNirmitha Herath
Sandrine Dufort, Cédric Louis Frédéric Boschetti
Acknowledgements
ANR P2N TheraGuIma (2011-2014)ANR RPIB MULTIMAGE (2013-2017)
BQR 2010, BQR PRES UB-UFC 2012, 2013
LTP project (2011-2014)
19
ANR RPIB MULTIMAGE (2013-2017)
EquipeX IMAPPI (2011-2019)
Défi G3N 2012
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