Nanoparticles and protontherapy
Y. Prezado on behalf of the collaboration
ISMO & ICPO & IMNC
Campus of Orsay
[email protected]
1
Interdisciplinary project aiming at finding improved therapies
for radioresistant tumors (e.g. gliomas)
Radiotherapy & nanoparticles
Physics
Biology
Chemistry
2
Radiotherapy (RT)
 Medical use of ionizing radiation for the treatment of cancer.
 One of the most important methods of cancer treatment
 Despite a rapid development in the last decades there is a still a
great need of research and development.
3
The rationale of radiotherapy
100 %
100%
Tumor Control
Probability
Normal Tissue
Complication
Probability
Dose
Radiotherapy and Nanoparticles (NPs)
Nanoparticles (NPs)
Nanoparticles (NPs)
Submicroscopic
particles of several
nanometers size.
Typically
Au, Pt, Gd,size
...
•Several :nanometres
Good candidates as a contrast agent,
•High
Z elements
Pt, Gd, …
drug
carriers
and Au,
radiosensitizers.
Hadron therapy Radiotherapy
and NPs
& nanoparticles
Spectacular
resultsresults
regarding
tumoral cell
death in photon
Spectacular
triggered
exploration
irradiations triggered their exploration in hadron therapy.
their effect is difficult to predict since it varies with
PioneerHowever,
experiment
cell line, NPs size, concentration, distribution inside the cell,
Hainfeldbeam
et al. “energy,
The useetc.
of gold nanoparticles to enhance radiotherapy in mice”,
PMB 2004.
53, Shanghai
June 12,
2014 + AuNP
Immaculada Martínez-Rovira
SubcutaneousPTCOG
tumors
RX– (250
kVp)
Page 1
A factor 4 increase in mean survival time
5
Mechanisms playing a role not yet clear
Physics: local dose enhancement?
Physics
Biology
Chemistry: chemical changes?
Production of harmful chemical species
by water radiolysis?
Biology: NPs produce cell arrest at radiosensitive
phases and oxidative stress (amplified with
irradiation)?
Combination of them? Weight of each process?
Chemistry
1. Overview
2. Multi-scale project
Nanoparticles and protontherapy: physical effects??
Plasmid DNA & NPs (Pt or Gd) + carbon
ions  amplification of biological damage:
factor 2 increase of DSBs
Porcel et al, Nanotechn. (2010)
tentatively ascribed to physical processes
(ionisations
and
electron
(auger)
emission) activated by incident ions and
secondary electrons emitted in the tracks
1. Overview
2. Multi-scale project
Nanoparticles and protontherapy
Projet “Improvement of the therapeutic index in protontherapy by means of
nanoparticles (Au & Gd)”
Multi-scale project IMNC & Protontherapy Center Orsay (ICPO) &
Institut Sciences Moleculaires (Orsay)
-In vitro (U87 human glioblastoma cells)
-In vivo (nude mice)
-Monte Carlo (MC) simulations to disentangle (and quantify) the physical
processes that might play a role
1. Overview
2. Multi-scale project
In vivo experiment
-Female nude mice (NMRI-Societé Janvier) 10 weeks
-U87 human glioblastoma grafted-subcutaneous in right
leg.
-Tumoral volume at irradiation: 200-250 mm3
Nanoparticles AGuiX (Gd) NanoH
45 minutes before irradiation
(estimated by MRI)
Intratumoral injection 50µl
of a solution at 100µM
Intravenous injection 150 µl
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1. Overview
2. Multi-scale project
In vivo experiment
Irradiations
Protons
Photons
E= 200 MeV
Dose rate: 2.3 Gy/min
Dose= 10 Gy
E= 78 keV
Dose rate = 0.9 Gy/min
Dose= 10 Gy
Series 1 (n=11)
Series 2 (n=12)
Series 3 (n=12)
Series 4 (n=12)
Series 5 (n=13)
Series 6 (n=13)
Series 7 (n=13)
Series 8 (n=13)
excipient 50 μL IT
AGuiX 50 μL IT
x-rays + excipient 50 μL IT
x-rays + AGuiX 50 μL IT
protons + excipient 50 μL IT
protons + AGuiX 50 μL IT
protons + excipient 150 μL IV
protons + AGuiX 150 μL IV
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1. Overview
2. Multi-scale project
2.2. In vivo experiment
1. Overview
2. Multi-scale project
2.2 In vivo experiment
C o u r b e s d e s u r v ie d e s a n im a u x p o s t t r a ite m e n ts
P o u r c e n t a g e d e s u r v ie
survie (jours)
groupes
Médiane de
100
v e h ic le
A G u lX
p h o to n s + v e h ic u l e
p h o to n s + A G u IX
50
p r o t o n s + v e h ic u le
p ro to n s + A G u IX
p r o t o n s + v e h ic u le
p ro to n s + A G u IX iv
0
0
20
40
60
j o u r s p o s t t r a it e m e n t s
80
excipient
12
AGulX
photons + excipient
12
24,5
photons + AGuIX
24,5
protons + excipient
protons + AGuIX
26
23
protons + excipient iv
! protons + AGuIX iv
24,5
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-No significant differences between the irradiated groups treated or not with NPs.
To be highlighted that in the group x-rays + NPs 2 animals alive for several months
with tumoral volume that does not evolve or decrease.
-Animals receiving IV died faster
1. Overview
2. Multi-scale project
In vivo experiment
Possible reasons?
• Dose delivered 10 Gy maybe too low … go up to 15 or 20 Gy?
• The cell line less suitable for sensitization?
• Time between injection and irradiation for a right NP internalization?
1. Overview
2. Multi-scale project
2.3. Monte Carlo simulations
-Monte Carlo (MC) simulations to disentangle (and quantify) the physical
processes that might play a role
MC code Gate 6.1 (Geant4.9.5)
Physics list
EM processes Livermore
Hadronic recommended by opengate collaboration
www.opengate.org
Energy cuts: the minimum for each type of interaction
Optimized step functions (0.2 0.0001 mm)
Geometry
Bragg Peak
200 MeV protons
400 nm
•
•
•
Macro
81 keV x-rays
V2: 0.5
nm
V1:0.5
nm
Beam size: 100 nm & 100 µm
10 μm/ AuNPs 3nm
0.2 mg/mL & 10 mg/mL
AuNp
3nm
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Increase of secondary electrons in presence of NPs
PHOTON
Concentration AuNp
(mg/mL)
PROTON
0,2
10
0,2
10
Secondary electrons (%)
0,40%
28,30%
0,00%
0,55%
Augers Electrons (%)
32.5%
1357%
0,00%
33%
E< 100 eV
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In vitro experiments NPs + proton irradiation
1
1
Survival Fraction
U87
U87 + AuNPs
U87 + GBNPs
0.1
0.1
0.01
0.01
0
1
2
3
4
5
Dose (Gy)
6
7
8
Radial distributions of energy deposited around the NP
Dose [a.u.]
Irradiation with 81 keV x-rays
AuNP
Water
Distance to NP (nm)
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Radial distributions of energy deposited around the NP
Irradiation with 200 MeV protons
Dose [a.u.]
AuNP
Water
Preliminary results
Distance to NP (nm)
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Perspectives and conclusions
Physical effects in proton therapy & nanoparticles do not seem to
play a major role
-Monte Carlo simulations including physical-chemistry
modeling are ongoing
Biochemical effects may be the responsible of (a part of) results
obtained
-On going studies employing infrared spectroscopy.
On going in vivo studies of NP distributions (MRI & PIXE)
Thank you very much for your attention
[email protected]