Pawel Olko Bronowice Cyclotron Centre, Institute of Nuclear Physics PAN, Kraków, Pol and

1. Nanoparticles for enhancing the effectiveness of proton therapy Pawel Olko Bronowice Cyclotron Centre, Institute of Nuclear Physics PAN, Kraków, Poland

2. Methods of cancer treatment • Surgery • Chemotherapy • Radiation therapy External radiotherapy Brachytherapy Targeted radiotherapy BNCT …….

3. Radiotherapy is not always successful • Glioblastoma • Pancreatic ductal adenocarcinoma • aggressive, • frequent recurrence • difficulties in diagnosis and treatment • enhanced tumour radio-resistance and low radiation tolerance of neighbouring healthytissu BNCT • Clinicalstudies with C-ions • Chiba, Japan • Heidelberg, Germany Is it possible to improve effectivness of proton therapy by introducing nanoparticles to target volume?

4. Outline • Rationale of proton therapy • Physics and microdosimetry of nanoparticles • Future work https://mappingignorance.org

5. Rationale of proton therapy • Dosedistribution • Verification • Lowscatteredradiation • Radiobiology Conformal dose distribution results in saving healthy tissue

6. Intensity Modulated Proton Therapy, IMPT Court. Engelsmann, PSI

7. Rationale of proton therapy • Dosedistribution • Verification • Lowscatteredradiation • Radiobiology Verification of range/ dose distribution using the PET/prompt gamma techniques

8. Rationale of proton therapy • Dosedistribution • Verification • Lowscatteredradiation • Radiobiology Distant doses from scattered radiation 10-100 times lower in PT than in classical MV X-rays

9. Rationale of proton therapy • Dosedistribution • Verification • Lowscatteredradiation • Radiobiology Protons Belli et al. 2000 Bettega et al. 1979 Relative Biological Effectivness increases for low energy protons

10. Proton therapy – low LET radiation? BEAM BEAM Secondary ions Protons L. Grzanka, NEUDOS-13, 2017

11. Can we locally increase energy deposition?

12. Boron Neutron Capture Therapy • 10B + nth → [11B] *→ α + 7Li + 2.31 MeV Ea = 1.47 MeV , Range ~ 9 um, LET~ 190 keV/um

13. Photon interactions with high Z elements – photoelectric effect Mass energy absorption coefficent for gold (Z=79)

14. Dose enhancement for orthovoltage X-rays on high-Z elements

15. Nanoparticles Particles: 1-100 nm Large surface as compared to total amount Mainly Ni, Fe, Au, Pt M. Parlińska, IFJ PAN

16. Nanoparticles Particles: 1-100 nm Large surface as compared to total amount Mainly Ni, Fe, Au, Pt M. Parlińska, IFJ PAN

17. Enhanced proton treatment in mouse tumors through proton irradiated nanoradiator effects on metallic nanoparticles Jong-Ki Kim et al., Phys. Med. Biol. 57 (2012) 8309–8323

18. Enhanced effectiveness of protons + nanoparticles Jong Ki Kim 2012 Phys Med. Biol. 57

19. Mechanism of dose amplification by gold nanoparticles, AuNP Jong Ki Kim 2012 Phys Med. Biol. 57

20. Mechanism of dose amplification by gold nanoparticles, AuNP Jong Ki Kim 2012 Phys Med. Biol. 57

21. Microdosimetry of low-energy photons P.Olko, Ph.D. thesis 1989 Low energy photons can enhanced RBE because of short, densely ionizing electron tracks

22. Spatial distribution of nanoparticles in biological cells - how does it influence the proton action Yuting Lin et al 2015 Phys. Med. Biol. 60 4149

23. Irradiation modalities: protons, MV X-rays and kV X-rays Yuting Lin et al 2015 Phys. Med. Biol. 60 4149

24. Local doses in the vicinity of gold nanoparticles (GNP) Yuting Lin et al 2015 Phys. Med. Biol. 60 4149 50 nm GNP protons For lower GNP diameters dose increases close to the surface

25. Cell survival after proton irradiation with gold nanoparticles (GNP) Yuting Lin et al 2015 Phys. Med. Biol. 60 4149 For the same weight the smallest GNPs are more effective

26. Cell survival after irradiation with gold nanoparticles (GNP) Yuting Lin et al 2015 Phys. Med. Biol. 60 4149 If NPs are not introduced in cell nucleus – no effect on survival

27. Survival for protons, 6 MV X-rays,250 kVp X-rays Yuting Lin et al 2015 Phys. Med. Biol. 60 4149 Protons and MV X-rays show equivalent survival only when the GNPs are in cell nucleus

28. Future work 1) New biofunctionalised NP 2) Cell radiobiology with NP 3) Radiobiology in animal models 4) Imaging NP transport with MRI 5) Microdosimetry of NP 6) TPS with included NP. modules

29. Future work 1) New biofunctionalised NP 2) Cell radiobiology with NP 3) Radiobiology in animal models 4) Imaging NP transport with MRI 5) Microdosimetry of NP 6) TPS with included NP. modules Uptake kinetic of the gadolinium based contrast agent in model tumour as assessed by 9.4T DCE MRI study at IFJ PAN [11].

30. Future work 1) New biofunctionalised NP 2) Cell radiobiology with NP 3) Radiobiology in animal models 4) Imaging NP transport with MRI 5) Microdosimetry of NP 6) TPS with included NP modules Alpha-particle and 3H tracks observed in LiF FNTD developed at IFJ PAN (Bilski & Marczewska, 2017

31. Future work 1) New biofunctionalised NP 2) Cell radiobiology with NP 3) Radiobiology in animal models 4) Imaging NP transport with MRI 5) Microdosimetry of NP 6) TPS with included NP modules TPS with option for calculation of enhanced RBE/dose due to proton interaction with NP

32. Thank you Acknowledgements to: M. Lekka, M. Parlińska, MPR Waligórski, W. Weglarz