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

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

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 healthy tissu BNCT Clinical studies with C-ions Chiba, Japan Heidelberg, Germany Is it possible to improve effectivness of proton therapy by introducing nanoparticles to target volume?

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

Rationale of proton therapy Dose distribution Verification Low scattered radiation Radiobiology Conformal dose distribution results in saving healthy tissue

Intensity Modulated Proton Therapy, IMPT Court. Engelsmann, PSI

Rationale of proton therapy Dose distribution Verification Low scattered radiation Radiobiology Verification of range/ dose distribution using the PET/prompt gamma techniques

Rationale of proton therapy Dose distribution Verification Low scattered radiation Radiobiology Distant doses from scattered radiation 10-100 times lower in PT than in classical MV X-rays

Rationale of proton therapy Dose distribution Verification Low scattered radiation Radiobiology Protons Belli et al. 2000 Bettega et al. 1979 Relative Biological Effectivness increases for low energy protons

Proton therapy – low LET radiation? BEAM BEAM Say the same configuration as before Nuclear reactions -> secondaries Explain LET method Secondary ions Protons L. Grzanka, NEUDOS-13, 2017

Can we locally increase energy deposition?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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].

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

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

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