EU PhD training : Marie Curie ITN ARGENT
Advanced Radiotherapy, Generated by Exploiting
Nanoprocesses and Technologies
September 2014 :
13 PhD positions in different fields :
-
Chemistry : synthesis, functionalization of NP
Physics / chemical physics (experimental/theory)
Medical physics/radiation physics
Biology (radiation)
Univ Paris Sud-Orsay (FR)
Open university (UK)
Queens university Belfast (UK)
Univ of Caen (FR)
Univ of Frankfurt FIAS (D)
Univ Madrid (S)
GSI (Darmstadt, D)
NanoH, SME (FR)
ChemaTech( SME, FR)
Quantumwise( SME, Danemrk)
Contact : sandrine.lacombe@u-psud.fr
RESEARCH
• Improvement of the hadrontherapy protocols using nanosensitizers (S. Lacombe Orsay)
• Uptake dynamics of nanoagents and effect on radioenhancement (Orsay/Belfast)
• Development of new modules for ATK code for modelling radiosensitizing nanoagents (A.
Solovyov/industrial in Danemark)
• Bond-breaking as a descriptor for nanodosimetry (G. Garcia-Madrid)
• Validation of models in medical radiation planning (G. Garcia, Madrid)
• Nanoagent functionalization aiming at tumor targeting and biocompatibility (industrial in France)
• Nanoscale understanding of cell signalling and biological response (K.Prise, Belfast)
• Multiscale understanding of radiation biodamage (A. Solovyov, Frankfurt and F. Curell, Belfast)
• Development of Lanthanides based nanosensitizers for theranostic ((industrial in France)
• Molecular efficiency of radiosensitizers in ion-induced radiation damage processes (B. Huber,
Caen)
• OER prediction on the nanoscale for a target tissue in different conditions of irradiation and
oxygenation (E. Scifoni, M. Durante, Darmstadt)
• Exploring site specificity, structure and sequence dependence of radiation-induced damage (N.
Mason, Milton Keynes)
• Impact of nanoscale processes and agents on biodamage complexity in the presence of
nanoagents (A. Solovyov, Frankfurt)
Contact : sandrine.lacombe@u-psud.fr
RESEARCH
• Improvement of the hadrontherapy protocols using nanosensitizers (S. Lacombe Orsay)
• Uptake dynamics of nanoagents and effect on radioenhancement (Orsay/Belfast)
• Development of new modules for ATK code for modelling radiosensitizing nanoagents (A.
Solovyov/industrial in Danemark)
• Bond-breaking as a descriptor for nanodosimetry (G. Garcia-Madrid)
• Validation of models in medical radiation planning (G. Garcia, Madrid)
• Nanoagent functionalization aiming at tumor targeting and biocompatibility (industrial in France)
• Nanoscale understanding of cell signalling and biological response (K.Prise, Belfast)
• Multiscale understanding of radiation biodamage (A. Solovyov, Frankfurt and F. Curell, Belfast)
• Development of Lanthanides based nanosensitizers for theranostic ((industrial in France)
• Molecular efficiency of radiosensitizers in ion-induced radiation damage processes (B. Huber,
Caen)
• OER prediction on the nanoscale for a target tissue in different conditions of irradiation and
oxygenation (E. Scifoni, M. Durante, Darmstadt)
• Exploring site specificity, structure and sequence dependence of radiation-induced damage (N.
Mason, Milton Keynes)
• Impact of nanoscale processes and agents on biodamage complexity in the presence of
nanoagents (A. Solovyov, Frankfurt)
SCIENTIFIC AND SOFT SKILLS:
3 months tutorials + soft skills (MBA 3 weeks) + 1 month industrial site
Contact : sandrine.lacombe@u-psud.fr
A roadmap for Europe’s research
on radiation damage
NANO - IBCT Sopot May 20 - 24 2013
Nigel Mason
The Open University
A history

How did we get to
be in SOPOT ?

Question (for
academics)

How many people
did you know in this
room in 2003 ?
Question for atomic molecular and
electron collisions people

In 2003 what did you know about DNA ?

Cells and radiotherapy ? RBE ? LET ? (Nano)
dosimetry

What molecular targets were you studying ?

ECAMP 2004 only 9/850 papers on biomolecules !
>20 on N2 and >100 on rare gases
Question for biological and clinical
people

In 2003 had you heard of DEA ?

Anions and Resonances ?

Did you know about experimental EU ion beam
facilities (GANIL, Groningen ? Had you visited
one ?
The conjecture

There has been a big change in what we study
and why !

A new (trans disciplinary) EU community has
developed.

It has been useful, successful and
The conjecture

There has been a big change in what we study
and why !

A new (trans disciplinary) EU community has
developed.

It has been useful, successful and
FUN
Where is all began (for many of us!)

The pioneering work of
Sanche et al and the
(in)famous Science paper

Resonant Formation of
DNA Strand Breaks by
Low-Energy (3 to 20eV)
Electrons. Science 287,
1658-1660 (2000). B.
Boudaiffa, P. Cloutier, D.
Hunting, M.A. Huels et L.
Sanche.
Strand breaks of DNA
10
DNA breaks per 104
incident electrons
10
5
SSB
DSB
e- + DNA → DNA-* → fragments
0
0
5
10
15
Electron Energy (eV)
L. Sanche et al. Science, 287 (2000) 1659 and PRL (2004)
20
These ‘fundamental’ studies coincided
with new therapies
e.g. carbon ion therapy. (Nano-IBCT)
Hence

The idea/development of need to bring two
disparate communities together

Atomic, molecular physics/ physical
chemistry

And

Radiation chemists/medical physics
This research has been developed
through networks
RADAM first COST Action

Presented 2002
WARSAW

Started 2003

RADAM 1 Lyons
2004
RADAM Meetings








1 2004 Lyons (food)
2 2005 Potsdam ( a tutorial)
3 2006 Groningen (Euro football!)
4 2007 Dublin (rain!)
5 2008 Debrecen (thunder!)
6 2009 Frankfurt
7 2010 Madrid
Then IBCT Nano Caen 2011 and Sopot 2013
The exchanges

RADAM; ECCL; EIPAM & Nano-IBCT has
supported

Over 450 visits/exchanges !!

They have built the community
So what have we learnt ?

DNA damage (key process) needs trans
disciplinary research
Lets look at interconnections in ‘RADAM’
community

To understanding DNA Damage (Solov’yov)
Energy loss by
the incident
particle
Propagation
in a dense
medium
Excitation of
the medium
Production of
Free Radicals
Solov’yov et al., Phys. Rev. E, v.79,
p. 011909-(1-7) (2009)
Europhysicsnews, v.40, n.2, p.21-24 (2009)
13 April 2015
Bragg peak, its position,
shape, and height
Energy spectrum,
number density, plasma
Production of
secondary
electrons, holes
Heating of
the medium
SSB’s and
DSB’s
Damage of the
DNA
Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)
MesoBioNano- Science Group @ FIASMesoBioNano(www.fias.uni-frankfurt.de/mbn)
Or view of Werner Friedland
physical track
structure
calculation
pre-chemical and
chemical stage
calculation
DNA target
modelling
biological
effect
simulation
Nano-ICBT 2011, Caen
Biological effect simulations using track structures
Track structure simulation …
based on cross sections for interactions of primary and secondary
ionising particles (electrons, photons, protons, alphas, ions)
… has to be complemented by target structure simulation …
where damage to DNA in the nucleus is - supposed to be - the main initiating
event by which radiation causes long-term harm to organs and tissues of the
body after low doses of radiation
… and by radiation effect simulation
where double-strand breaks (DSB) in genomic DNA are – supposed to be crucial initial lesions for causing critical damage after irradiation
Nano-ICBT 2011, Caen
Where are we now ?

Our studies in the mechanisms of radiation
damage has developed rapidly in the last decade.

There has been a lot of work on the fragmentation
(and hence stability) of biomolecules
In particular DEA
(>80% of molecular targets for which DEA has been
explored are biomolecules and studied since 2002 !)

Bond Selectivity using Electrons
Process of Dissociative Electron Attachment
DEA

Is a universal process
 Often simple H abstraction (M-H)
and is bond specific !
DEA to biomolecules typical results -- S Ptasinska
Thymine + e-
→ TNI-*
→
C5H6N2O2-
126 amu
electron attachment
e
125 amu
→ (T-H)- + H
→ (T-2H)- + neutral(s) 124 amu
→ C4H5N2O- + neutral(s) 99 amu
→ C2H3N2O- + neutral(s) 73 amu
→ C3H2NO- + neutral(s) 68 amu
→ C3H4N- + neutral(s) 54 amu
→ OCN- + neutral(s) 42 amu
→ CN- + neutral(s) 26 amu
→ O- + neutral(s) 16 amu
→ H- + neutral(s)
1 amu
dissociative electron attachment
Cross section (10-20 m2)
DEA in Thymine
(M-H)-
12
125 amu
e
10
8
6
4
H loss
2
0
0
1
2
3
Electron energy (eV)
4
DEA

But what is real relevance to the cell biology ?

Does it hold in condensed phase ?

Can it explain any radiobiology phenomena ?
(e.g radiosensitizers)
3
Rendement ( x10 counts)
Desorption of anions and
neutrals from Tetrahydrofuran
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
CHO
140
120
100
80
60
40
20
0
-20
4
-
H
H3C2O
3
-
2
-17
2
P (x 10 cm )
1
0
8
7
6
5
4
3
2
1
0
Formation de C=O
THF (4 layers) / Kr / Pt(111)
2
4
6
8
10 12 14 16 18 20 22 24 26
Energie d'électron incident (eV)
Uracil
Thymine
Bromouracil
(Radiosensitizer)
Freie University
Berlin
 ≈ 600 Å2
.
+ Br
Ion impact

Similar story to electrons/DEA

Great progress in number of systems studied
and exploration of fragmentation
Stability - necleobases more stable than sugars
(e.g. uracil cf deoxyribose) (Hoekstra)

• Groningen University
• Ion irradiation of
biomolecules
• Eg C+ on nucleobases
Deoxyribose and amino
acids
• Different fragmentation
patterns
Ion impact

But ….

Can this be extrapolated to cellular conditions
and condensed phase ?)

What is relevance of heavy ions (> Carbon ?)
Photon impact

Photostability

Electronic state
structure of
biomolecules

Quantum chemistry
advances (DFT)
Three Grand Challenges of the
underpinning fundamental science
1.
Moving from the isolated gas phase to the
cellular environment
2.
Extend study of damage to DNA to other
macromolecules in the cell and cell itself
1.
Developing models of such damage for use in
therapy etc.
Moving from the isolated gas phase to the cellular
environment
• Developing cluster
sources
• e.g. nucleobases and
water (S Eden OU)
• Study spectroscopy
• Collision dynamics
• PDRA post on offer
Neutralise the
selected cluster
anions *
Range of
neutral
clusters
Range of
cluster
anions
Select one
cluster
anion m/q
EA to selected
neutral clusters
or REMPI (laser
not shown)
TOF mass
spectrometer
Remove
remaining
anions
Faraday
cup
CW helium expansion
seeded with molecules
Quadrupole
Electron beam
(<1 eV)
1) Cluster source
Electrostatic
deflector
CW laser for electron
photo-detachment
Electron
monochromator
2) Neutral target selection
3A) EA-TOF or REMPI-TOF
* Key challenge: avoid dissociation at neutralisation step
Also available: 3B) REMPI-TOF only
Developments in understanding of fundamental
processes is used to develop better models
Allowed new track models to be developed
Track modelling
5 single tracks
Auger
Neutral
dissociation
Ionisation
2 keV electrons in H2O
Pressure: 200 Torr
Excitation
Such models need
 Cross
 Real
sections !!!!
numbers not just
phenomenology !
Planning a Database
Data providers
* theory
* experiment
Data provided
Data
requested
Data users in various
application fields
* fusion science
* astrophysics
* industrial plasmas
* environmental physics
* medical (radiotherapy)
etc.
Data centers
data compilation
data evaluation (important but not easy)
dissemination and updating of database
retrievable online database
= easy to access, use, find data
International A&M
data center network
IAEA, NIFS, A-PAN,
KAERI, NIST, ORNL,
GAPHIOR, VAMDC,
Electron interactions data
in H2O
eMOL data review and
validation project
Summary of the Recommended data
on the electron collision cross section for H2O
Y. Itikawa and N.J.Mason, J. Phys. Chem. Ref. Data 34 (2005)1
e-H2O integral cross section data
(Courtesy of G Garcia)
Total scattering
1000
(5%)
Cross section (a02)
100
Integral elastic
and inelastic
10
(10%)
1
Ionisation (7%)
Excitation (15%)
0.1
Neutral
dissociation
0.01
1
10
100
1000
Electron energy (eV)
10000
(15%)
But such complete data sets are rare
For most biomolecules MOST cross sections are missing
Some may be calculated – eg ionisation
(Theory – Kim (BE) and Deutsch Maerk )
And compare well with experiments
Or for total, elastic, some excitations
Quantemol package (J Tennyson)
So lots of data needed !

How do we co-ordinate data collection ?

Where does the user find it ?

When collected how/where is it stored and
‘ratified’ ?

VAMDC will provide a one stop scientific
data e-infrastructure enabling easy access to
A+M data
www.vamdc.org

To include RADAM database from COST
Nano-IBCT network
But beyond this….

Need to remember the chemistry

And biology ……..
Particle tracks during physico-chemical and chemical stage
physical
stage
esub ,H2O+
A1B1, B1A1
Ryd, db
10-15 – 10-12 s
• relax
• auto-ionize
• dissociate
H2O+ + H2O → H3O+ + •OH
• diffuse
• react
eaq, •OH, H•, H2
H3O+ , OH- , H2O2
H2O + DE
H• + •OH
B1A1 →
H2O + DE
H3O+ + •OH + eaq
H2 + •OH + •OH
Ryd,db → H2O + DE
H3O+ + •OH + eaq
A1B1 →
physicochemical
10-12 – 10-6 s
35%
65%
30%
55%
15%
50%
50%
100%
Nano-ICBT 2011, Caen
chemical
stage
reaction rate
diffusion
coefficients D constants k
eaq + eaq + 2H2O
eaq + •OH
eaq + H• + H2O
eaq + H3O+
eaq + H2O2
•OH + •OH
•OH + H•
H• + H•
H3O+ + OH-
→ H2 + 2OH→ OH→ H2 + OH→ H• + H2O
→ OH- + •OH
→ H2O2
→ H2O
→ H2
→ 2H2O
Radiation damage to DNA
Damage of the genome in
living cell by ionising
radiation is about 1/3 a
direct and 2/3 an indirect
processes.
DNA damage signalling in bystander cells
Burdak-Rothkamm and Prise, 2009
Nucleosome damage by shock wave
•
•
•
•
•
•
•
•
•
•
R=17.5nm
L=8nm
# atoms ~ 700.000
T0=310 K
NVE ensemble
Z-periodic BC
Integration timestep 0.1 fs
CHARMM22 ForceField
TIP3P model for water
…
Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)
MesoBioNano- Science Group @ FIASMesoBioNano(www.fias.uni-frankfurt.de/mbn)
DSB repair model adapted to Stenerlöw data
Italic numbers are time constants in seconds
(1) Chromatin remodeling
(2) DSB formation from labile sites
(3) Processing of DSB from labile sites before
synapsis
(4) Inhibition of Ku70/Ku80 attachment
(5) Release from Ku70/Ku80 attachment inhibition
(6) Ku70/Ku80 attachment to DNA
(7) Ku70/Ku80-DNA dissociation
(8) DNA-PKcs attachment to DNA
(9) DNA-PK – DNA dissociation
(10) Synapsis
(11) Phosphorylation, recruitment and action
of nucleases, polymerases, ligases
(12) Cleaning of single-strand breaks and
base lesions
(13) Final ligation and removal of repair enzymes
(14) Inhibition of final ligation
(15) Release form inhibition of final ligation
(a) Correct rejoining
(b) Incorrect joining other than (c) and (d)
(c) Ring formation
(d) Chromosomal exchange aberration
Nano-ICBT 2011, Caen
Other challenges
Developing new radiosensitizers
e.g. Au nanoparticles
Sensitising effects of GNPs: the role of Auger
electrons
Fred J. Currell, Kevin M. Prise et al,
Nature Scientific Reports (2011)
Here, the data are used to investigate whether the model presented
by Fred J. Currell et al, Nature Scientific Reports (2011) is capable
of accurately quantifying the sensitising effects of GNPs.
Average energy deposit in the vicinity of a 20 nm
GNP after a single ionizing event by a photon
Science Group @ FIAS (www.fias.uni-frankfurt.de/mbn)
MesoBioNano- Science Group @ FIASMesoBioNano(www.fias.uni-frankfurt.de/mbn)
EU PhD training : Marie Curie ITN ARGENT
Advanced Radiotherapy, Generated by Exploiting
Nanoprocesses and Technologies
13 PhD positions in different fields :
Applications procedure starting September 2013
Starting date : September 2014
Contact : sandrine.lacombe@u-psud.fr
And we have more to explore with
new projectiles
• What about damage
induced by positrons
??
• How do positrons
damage DNA ?
• Role of annihilation
and gamma rays ?
What is the role of water and proteins in electron induced
damage of DNA?
DNA
• Free electron attachment to aminoacids/nucleobases complexes
DNA
• radiation damage of proteins
radiation
proteins
Proteins
(amino acids)
bases
proteins
sugar
undamage
atoms
undamage
atoms
M. Begusova et al., Int. J.Radiat.Biol. (2003)
What is the effect of damage to the cell membrane ?
• radiation damage of proteins
DNA structures and nanotechnology
• Making DNA wires
• Adding metal atoms
to make DNA
conduct
• Electron transport =
electron induced
damage
DNA structures
Recent work in the
Turberfield group Oxford
includes the design and
characterization of DNA
tetrahedra.
Which can serve as rigid
building blocks and as
molecular cages;
and the application of DNA
lattices to protein structure
determination.
Plasma treatment
DNA Damage (SSB DSB)
induced by
VUV, electrons
Ions and plasmas
S Ptasinska talk to follow
And related fields
ASTROBIOLOGY
Stability and development of biomolecules,
cells and DNA
Space medicine

Survival in space

Travel to Mars
3 years – lethal dose
of radiation to solve

Horizon 2020

Fast approaching
Programmes in health, Radiation (Euratom),
Space and nanomaterials

All relevant to us
Horizon 2020

So lets be ready to work together to exploit it

What is next ?? (COST March 2014 !)
But more …..
I propose (through NANO IBCT) we copy
Astrobiology community and
Write a roadmap
Awe asking the right questions ?
Roadmap
• Review where we are
• Declare the challenges
• Propose how the challenges are met (by
integrated research plan)
• Publish and so define the road ahead