Radiobiology Research with Laser Driven Ionizing Radiation (LDIR) - - PowerPoint PPT Presentation

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Radiobiology Research with Laser Driven Ionizing Radiation (LDIR) Katalin Hideghty , Rita Emilia Szab , Rbert Polanek, Zoltn Szab , Szilvia Brunner, Tnde Tks EUCALL Workshop: Biology at Advanced Laser Light Sources European X-ray

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Radiobiology Research with Laser Driven Ionizing Radiation (LDIR)

Katalin Hideghéty, Rita Emilia Szabó, Róbert Polanek, Zoltán Szabó, Szilvia Brunner, Tünde Tőkés

EUCALL Workshop: Biology at Advanced Laser Light Sources European X-ray FEL, Schenefeld, Germany, 2017

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Complex tumor therapy

Radiotherapy Surgery Chemotherapy Targetted therapy Immuno therapy

Advanced diagnostics

Improved

  • utcome
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Ionizing radiation effects in space and time

Immuno- activation 10-15

10-12

10-9 10-6 10-3 sec

From atomic- ,molecular level to whole body

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Timing

Fractionation Hypo-, Hyperfract. Acceleration (CHART) Prolongation Flash

Combined treatment

sensitisation/protection

Chemo-, hormon, biol.m., hypoxic RT-sensit., immunth.

Technical development

Conformal RT, IMRT, IGRT, dose painting HadronRT, MRT, BNCT, BPF

Increase of the therapeutic ratio

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Hadron therapy

new gen. part. acc 3DCRT, IMRT, SRS/ SBRT/ SABR

IGRT Motion control Selectivity, accuracy (mm), beam quality divergence, dose rate (10Gy/min) 120 years photons/electrons

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Mainly inidrect action

  • OH

Low LET Isolated lesions High LET Clustered lesions

Very dense ionisation High RBE Low OER

Dose depth curves

Combination with immunotherapy

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1st Hospital based facility

60 years

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Mainly inidrect action

  • OH

Low LET Isolated lesions High LET Clustered lesions

Very dense ionisation High RBE Low OER

Linear energy transfer LET

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>25000

MedAustron, Austria

30 years

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Fixed Field Alternating Gradient

Compact EIMCPT design

Proton/ion acceleration techniqes

http://phys.org/news/2014-06-compact- proton-therapy-cancer.html

Compact superconducting synchro-cyclotrons (IBA, Varian, Mevion) provide a KHz proton source with nanoampere current with 34 to 250 MeV

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Hadron centers

54 centers are in operation and further 40 is planned

<2% of all RT

>200000

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Favaudon V, Fouillade C, Vozenin MC Ultrahigh dose-rate, "flash" irradiation minimizes the side-effects of radiotherapy] Cancer Radiother. 2015 Oct;19(6- 7):526-31

A 17 Gy conventional irradiation induced pulmonary fibrosis and activation of the TGF-beta cascade in 100% of the animals 24-36 weeks post-treatment, as expected, whereas no animal developed complications below 23 Gy flash irradiation, and a 30 Gy flash irradiation was required to induce the same extent of fibrosis as 17 Gy conventional irradiation. FLASH irradiation: <500ms pulses of >40 Gy/s

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MRT: spatially fractionated, planar x-ray (50-600keV) /proton/electron/ 25-75 micron-wide beams, with a very sharp penumbra, separated by several times of their beam width.

Synchrotron-based Microbeam radiation therapy (MRT) Under preclinical evaluation

Zhang et al. Expert Rev Anticancer Ther. 2015 December

Dose profiles of alternating peaks and valleys with high peak-to-valley-dose-ratios (PVDR)

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  • C. Fernandez-Palomo, C. Mothersill, E. Bräuer-Krisch, J. Laissue, C. Seymour, E. Schültke: γ-

H2AX as a Marker for Dose Deposition in the Brain of Wistar Rats after Synchrotron Microbeam Radiation PLoS ONE 10(3): e0119924. 2015

Synchrotron-based MRT resulted in 10 fold prolonged survival of the treated animals with brain tumor xenograft

Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents.

  • E. Brauer-Krisch a, J-F.s Adam et al. Medical physics aspects of the synchrotron radiation

therapies:Microbeam radiation therapy (MRT) and synchrotron stereotactic radiotherapy (SSRT) Physica Medica 31 (2015) 568e583

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Physiologically gated microbeam radiation using a field emission x-ray source array Donzelli et al.: Conformal image-guided MRT at the ESRF With the implementation of conformal image-guided MRT, the treatment of deep-seated tumors in large animals will be possible for multiple port irradiations.

MRT

Daniele Pelliccia, Jeffrey C Crosbie, and Kieran G Larkin Phase contrast image guidance for synchrotron microbeam radiotherapy Physics in Medicine & Biology

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Thermal neutrons captured by high probability by 10B desintegrates into two particles .

Boron Neutron Capture Therapy (BNCT)

The two particles α and 7Li absorption ranges in tissue (~9 mm and ~5 mm respectively). All the energy is released inside the tumor cell

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High LET, dense ionization High RBE Low OAR Binary approach

BNCT Selective, cell-targetted energy deposition

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  • Low systemic toxicity
  • Selective uptake into the tumour cells
  • Rapid clearance from normal tissues
  • High intratumoural concentration (20 μg/gTumor)/
  • >100 ppm)
  • Favourable intracellular distribution (preferably in the

cell nucleus)

Requirements on the 10B carriers

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Neutron beam requirements for BNCT

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Dose components DBoron DNitrogen DPhoton Dneutron

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Clinical application of BNCT

N>200

10B carrier BSH Na2B12H11SH HFR Research reactor Recurrent H&N tumors 10B carrier: BPA

Boro-phenylalanin

Malignant melanoma 10B carrier: BPA+BSH Extracorporal liver BNCT

BPA

50 years

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Neutron sources for BNCT

Nuclear reactors Charged particle accelerators Compact neutron generators LINAC based neutron source High power laser facilities may provide via (p, n) reaction intense epithermal neutron beam

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.

BPF 11B (p, 3α) reaction occurs between protons and boron-11, without producing high-energy neutrons

Boron Proton Fusion Reaction

The highest cross-section of this reaction

  • ccurs with protons having energies

around 600-700 keV corresponding to the Bragg peak Research on nuclear fusion energy production

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Yoon DK, Jung JY, Suh TS. Application of proton boron fusion reaction to

radiation therapy: a Monte Carlo simulation study. Appl Phys Lett. 2014;105:223507.

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  • D. Adam and B. Bednarz, SU-F-T-140: Assessment of the proton boron fusion

reaction for practical radiation therapy applications using MCNP6, Med. Phys. 43 (2016) 3494 Jung JY, Yoon DK, Barraclough B, Lee HC, Suh TS, Lu B Comparison between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT): a Monte Carlo study. Oncotarget. 2017 Feb 25 GAP Cirrone L Manti, D Margarone, L Giuffrida, A. Picciotto, G. Cuttone, G. Korn, V. Marchese, G. Milluzzo, G. Petringa, F. Perozziello, F. Romano, V. Scuderi, Nuclear fusion enhances cancer cell killing efficacy in a protontherapy model Med. Phys: submitted on 22. 01 2017

In silico- and in vitro studies on BPFEPT

Both chromosoma abberation analysis and colony forming assay confirmed the enhanced effectivity of BPR in cell cultures using natural (80% 11B containing) BSH at a 62 MeV proton source

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PBR Enhanced Proton Therapy PBREPT

In addition to selective proton therapy High spatial resolution High LET, High RBE Low OAR Binary approach

11B 11B 11B 11B 11B 11B

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Dose- and LET-painting with PBFEPT

LET-painting increases tumour control probability in hypoxic tumours

  • N. BASSLER J.TOFTEGAARD et al.

Acta Oncologica

Simultaneous dose and LET

  • ptimisation has a potential to achieve

higher tumour control and/or reduced normal tissue control probability.

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BPFEPT

Additional values

High LET radiation in combination immunotherapy is a highly promising new approach RT Paradigm shift: local systemic effect

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Exploring the potential of LDIR RADIOBIOLOGY Laser-electron beam Laser-proton/ion beam Laser - neutron beam

Conventional RT sources

SETUP DESIGN, DOSIMETRY, DOSE CALCULATION, Effects on normal tissue / tumor response RBE of pulsed, ultraintense beams MRT Flash BNCT, BPREPT

10B/11B carriers

Ultra short pulse - time resolution Ultrahigh dose rate Extreme small beam – spatial resolution High repetition rate

Effective, safe application

As referrence radiation for comparison

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Exploring the potential of LDIR RADIOBIOLOGY

Laser-electron beam Laser-proton/ion beam Laser - neutron beam

Conventional RT sources

SETUP DESIGN, DOSIMETRY, DOSE CALCULATION, Effects on normal tissue / tumor response RBE of pulsed, ultraintense beams MRT Flash

Classic In vitro and in vivo biological systems Assessment of morphologic, functional, cellular, molecular changes

  • f different normal tissue and tumor models

Development of novel vertebrate model BNCT, BPREPT

10B/11B carriers

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50 100 150 200 250 300 5 10

Kolóniák száma Dose (Gy)

Colony forming assay

0% 50% 100% 5 10

Dose (Gy)

MTS assay

Mán I, Plangár I, Szabó ER, Tőkés T, Szabó Z, Nagy Z, Fekete G, Mózes P, Puskás LG, Hideghéty K, Hackler L Jr Dynamic monitoring of ionizing radiation effect using a Novel Real-Time Cell Analysis Platform Mol Med Rep. 2015 Sep;12(3):4610-9

Traditonal in vitro model cell cultures

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Anaesthesia: i.p. chloral-hydrate Positioning: special bunk-bed Source: 1,26 MeV energy Cobalt Dose: 40 Gy (2x20Gy) Irradiation: 10 mm diameter collimator, homogen irradiation of hippocampus (at both hemispheres)

Rat model for focal brain injury

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Mouse experiments with electron beam

Anaesthesia: i.p. chloral-hydrate Positioning: on one side Source: 6 MeV energy Siemens linear accelerator Dose: 40 Gy Irradiation: 5 mm diameter collimator

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Anaesthesia: i.p. chloral-hydrate Positioning: special bunk-bed Source: 6 MeV energy Siemens linear accelerator Dose: 40 Gy Irradiation: 10 mm diameter collimator, homogen irradiation of hippocampus (at one hemisphere)

Research on RBE using RT modifying angents

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Neurofunctional tests

Morris Water maze Open-field test Passive avoidance

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Histopathological evaluation of effects of focal brain irradiation

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Exploring the potential of LDIR RADIOBIOLOGY

Laser-electron beam Laser-proton/ion beam Laser - neutron beam

Conventional RT sources

SETUP DESIGN, DOSIMETRY, DOSE CALCULATION, Effects on normal tissue / tumor response RBE of pulsed, ultraintense beams MRT Flash

Classic In vitro and in vivo biological systems

Assessment of morphologic, functional, cellular, molecular changes

  • f different normal tissue and tumor models

Development of novel vertebrate model

BNCT, BPREPT

10B/11B carriers

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Novel vertebrate model for radiobiology

Zebrafish (Danio rerio):

  • Easy to handle, good reproduction captivity
  • embryo and larva body transparency
  • external fertilization
  • rapid embryonic development
  • genomic similarity to the human genome
  • the complete genome sequence was published (2013)
  • Availability of several transgenic lines
  • high resilience.
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  • Size of the embryos and larvae is 0.5-2 mm
  • Can be kept in standard plates (4-96 wells) and

plastic bags, eppendorf tubes

  • Rapid development

Embyo size is corresponding to a 3D cell culture size (4-500um)

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Irradiation of zebrafish embryos

Wild type zebrafish embrios (24 hpf) were irradiated with photons at 5 - 20 Gy dose and reactor/cyclotron neutron-photon mixed beam at 1-8 Gy dose

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End points of zebrafish embryo experiments detection of malformation and survival

Control 5 Gy 10 Gy 15 Gy 20 Gy

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Survival and malformation depending on the age of the embryo

6 hpf

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Survival % Control 5 Gy 10 Gy 15 Gy 20 Gy

  • 20,00

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Distortion % KO 5 Gy 10 Gy 15 Gy 20 Gy

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Survival % Control 5 Gy 10 Gy 15 Gy 20 Gy

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Distortion % KO 5 Gy 10 Gy 15 Gy 20 Gy

24 hpf

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0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Survival % Control 5 Gy 10 Gy 15 Gy 20 Gy

  • 20,00

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Distortion % KO 5 Gy 10 Gy 15 Gy 20 Gy

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Survival % Control 5 Gy 10 Gy 15 Gy 20 Gy

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7 Time (dpf) Distortion % KO 5 Gy 10 Gy 15 Gy 20 Gy

6 hpf 24 hpf

Testing of the potential radioprotective agent L-alpha glycerylphosphoryl-choline in a zebrafish embryo model Szabó ER, Plangár I, Mán I, Daróczi B, Tőkés T, Szabó Z, Fekete G,

Kovács R, Baska F, Boros M, Hideghéty 2016 Zebrafish Res.

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Survival, malformation of different beams for RBE definition

0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7

Survival % Time (dpf)

CO 5 GY 10 Gy 15 Gy 20 Gy 0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7

Survival % Time (dpf)

CO 1,25 Gy 1,875 Gy 2 Gy 2,5 Gy 0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7

Distortion % Time (dpf)

CO 5 GY 10 GY 15 GY 20 GY 0,00 20,00 40,00 60,00 80,00 100,00 1 2 3 4 5 6 7

Distortion % Time (dpf)

CO 1,25 Gy 1,875 Gy 2 Gy 2,5 Gy

Photon Neutron

RBE= LD50ph/LD50n= 20/2=10

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Macroscopic morphological abnormalities of the zebrafish embryos

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Distance between the two ends of the embryo

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Diameter of the Yolk sac

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Diameter and circumference of the eye

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1 film: 1.86 +- 0.075Gy

Feasibility study at the proton source

  • f the LION Facility Munnich

36+ 18 hours transport, 10 hours at the laser facility was well tolerated The system is highly adaptable to the industrial conditions, and to the limitations of the beam (direction, energy, size)

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micro-ophthalmia

30-24/ 6 bad shots

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Microscopic lesions of the zebrafish embryos

Control After 10 Gy

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Inflammatory cytokine expression

(RTPCR)

Tissue interleukin-1β levels Tissue NFκB levels

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The development of high power laser driven particle acceleration (VHEE, proton, neutron) with ultrahigh time and space resolution, could accelerate the implementation of promising novel methods

  • energy modulation, high resolution IMRT
  • multi particle beam radiation,
  • Microbeam radiotherapy MRT,
  • -Flash RT
  • BNCT , BPF enhanced proton therapy

Intensive radiobiology research is essential to explore, and

  • ptimize these techniques for clinical application.

We propose a new vertebrate model (zebrafish embryo) for preclinical radiobiological research at laser facilities.

Conclusions

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PATHOLOGY Histology, immunohistochem RADIOLOGY small animal MRI DERMATOLOG Y Cellculture and genetic lab

ONCOTHERAPY Dosimetry

LINAC ref. foton, electron

radiation

EXPERIMENTAL SURGERY

  • Radbiol. Lab.,

malonaldehyd..

PHYSIOLOGY neurovascular function

Univ.Gödöllő

Fish laboratory Proton (IBA) OncoRay Laser driven proton beam HZDR

Laser driven proton beam LMU, Munnich

MEDICAL PHYSICS AND INFORMATICS Fish lab. Chemical

  • dosimetry. RT

planning,

PHARMAC OGNOSIA Radiation modifyers

Neutron beam KFKI/BME Research reactor ATOMKI cyclotron Neutron/proton

Laser driven proton beam ELI-Beamline, Prague

Collaboration on Radiobiology

Zebrafish embryo model is proposed for radiobiology research at laser driven ionizing radiation sources and for intercomparison on the biological effectiveness of the laser accelerated particle beams at different centres

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THANK YOU FOR YOUR ATTENTION!

The ELI-ALPS project (GOP-1.1.1-12/B-2012-000, GINOP-2.3.6-15-2015-00001) is supported by the European Union and co-financed by the European Regional Development Fund.

  • Dr. Szabolcs Czifrus
  • Dr. CsillaPesznyák
  • Dr. András Fenyvesi
  • Dr. József Molnár
  • Dr. Jörg Pawelke
  • Dr. Elke Beyreuther
  • Dr. Jörg Schreiber
  • Dr. Daniel Haffa

Fodor Emese

  • Dr. Varga Zoltán

Szigeti Erika Függ Róbertné Dr.Reisz Zita Prof.Dr. Bata –CsörgőZsuzsanna Diósi Ákos Katona Melinda