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
Complex tumor therapy Targetted therapy Immuno therapy Improved Advanced Radiotherapy Chemotherapy outcome diagnostics Surgery
Ionizing radiation effects in From atomic- ,molecular space and time level to whole body 10 -12 10 -3 sec 10 -15 10 -9 10 -6 Immuno- activation
Increase of the therapeutic ratio Timing Fractionation Hypo-, Hyperfract. Acceleration (CHART) Prolongation Flash Combined treatment Technical development sensitisation/protection Conformal RT, IMRT, IGRT, dose painting Chemo-, hormon, biol.m., hypoxic RT-sensit., immunth. HadronRT, MRT, BNCT, BPF
120 years photons/electrons 3DCRT, IMRT, SRS/ SBRT/ SABR Selectivity, accuracy (mm), beam quality divergence, dose rate (10Gy/min) IGRT Hadron therapy new gen. part. acc Motion control
Dose depth curves Low LET High LET - OH Very dense ionisation Mainly inidrect action Clustered lesions High RBE Isolated lesions Low OER Combination with immunotherapy
60 years 1st Hospital based facility
Linear energy transfer LET Low LET High LET - OH Very dense ionisation Mainly inidrect action Clustered lesions High RBE Isolated lesions Low OER
30 years MedAustron, Austria >25000
Proton/ion acceleration techniqes Compact EIMCPT design 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 Fixed Field Alternating with 34 to 250 MeV Gradient
Hadron centers 54 centers are in operation and further 40 is planned >200000 <2% of all RT
FLASH irradiation: <500ms pulses of >40 Gy/s 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 . 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
Synchrotron-based Microbeam radiation therapy (MRT) Under preclinical evaluation 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. Dose profiles of alternating peaks and valleys with high peak-to-valley-dose-ratios (PVDR) Zhang et al. Expert Rev Anticancer Ther . 2015 December
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 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
MRT 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. Physiologically gated microbeam radiation using a field emission x-ray source array Daniele Pelliccia, Jeffrey C Crosbie , and Kieran G Larkin Phase contrast image guidance for synchrotron microbeam radiotherapy Physics in Medicine & Biology
Boron Neutron Capture Therapy (BNCT) Thermal neutrons captured by high probability by 10 B desintegrates into two particles . 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
BNCT Selective, cell-targetted energy deposition High LET, dense ionization High RBE Low OAR Binary approach
Requirements on the 10 B carriers • Low systemic toxicity • Selective uptake into the tumour cells • Rapid clearance from normal tissues • High intratumoural concentration (20 μ g/gTumor)/ • >100 ppm) • Favourable intracellular distribution (preferably in the cell nucleus)
Neutron beam requirements for BNCT
Dose components D Boron D Nitrogen D Photon D neutron
Clinical application of BNCT 50 years N>200 Malignant melanoma 10B carrier: BPA+BSH Extracorporal liver BNCT BPA HFR Research reactor 10B carrier BSH Recurrent Na 2 B 12 H 11 SH H&N tumors 10B carrier: BPA Boro-phenylalanin
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
Boron Proton Fusion Reaction Research on nuclear fusion energy production BPF 11 B (p, 3α) reaction occurs between protons and boron-11, without producing high-energy neutrons . The highest cross-section of this reaction occurs with protons having energies around 600-700 keV corresponding to the Bragg peak
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.
In silico- and in vitro studies on BPFEPT 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 Both chromosoma abberation analysis and colony forming assay confirmed the enhanced effectivity of BPR in cell cultures using natural (80% 11 B containing) BSH at a 62 MeV proton source
PBR Enhanced Proton Therapy PBREPT 11 B 11 B In addition to selective 11 B 11 B proton therapy 11 B High spatial resolution 11 B High LET, High RBE Low OAR Binary approach
Dose- and LET-painting with PBFEPT Simultaneous dose and LET optimisation has a potential to achieve higher tumour control and/or reduced normal tissue control probability. LET-painting increases tumour control probability in hypoxic tumours N. BASSLER J.TOFTEGAARD et al. Acta Oncologica
Additional values BPFEPT High LET radiation in combination immunotherapy is a highly promising new approach RT Paradigm shift: local systemic effect
Exploring the potential of LDIR RADIOBIOLOGY Laser-electron Laser-proton/ion Conventional RT Laser - neutron sources beam beam beam Ultra short pulse - time resolution As referrence Ultrahigh dose rate radiation for Extreme small beam – spatial resolution comparison High repetition rate SETUP DESIGN, DOSIMETRY, DOSE CALCULATION, Effects on normal BNCT, MRT RBE of pulsed, tissue / tumor BPREPT Flash ultraintense 10 B/ 11 B carriers response beams Effective, safe application
Exploring the potential of LDIR RADIOBIOLOGY Laser-proton/ion Laser-electron Laser - neutron Conventional beam beam beam RT sources SETUP DESIGN, DOSIMETRY, DOSE CALCULATION, Effects on normal BNCT, MRT RBE of pulsed, tissue / tumor BPREPT Flash ultraintense 10 B/ 11 B carriers response beams Classic In vitro and in vivo biological systems Development of novel vertebrate model Assessment of morphologic, functional, cellular, molecular changes of different normal tissue and tumor models
Traditonal in vitro model cell cultures Colony forming assay MTS assay 300 Kolóniák száma 100% 250 200 150 50% 100 50 0 0% 0 5 10 0 5 10 Dose (Gy) Dose (Gy) 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
Rat model for focal brain injury 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)
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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