Metallic nanoparticles in proton therapy: how does it work? Dr. Anne-Catherine Heuskin University of Namur 3 rd BHTC workshop

Transcription

1 Metallic nanoparticles in proton therapy: how does it work? Dr. Anne-Catherine Heuskin University of Namur 3 rd BHTC workshop

2 SF Why do we use nanoparticles in radiation therapy? Grail increase biological effects in tumors and spare healthy tissues 1 RARAF 1Gy/min - UNamur CL RARAF 8.7 Gy/min - RARAF CL RARAF 0.1 Gy/min - UNamur CL UNamur 1 Gy/min - UNamur CL Healthy cells 0,1 A549 - a (100 kev/µm) 0,01 Cancerous cells 0,0 0,5 1,0 1,5 2,0 Dose (Gy)

3 Nanoparticle sensitizers Dorsey et al. Transl Cancer Res 2013

4 Evidence with X-rays Bladder cancer cells with 250 kvp X-rays and 50 nm GNPs Glioma cells with 4 Gy X-rays Jeynes et al. Phys Med Biol 2014 Dorsey et al. Transl Cancer Res 2013

5 Evidence with X-rays Mice with GBM and 20 Gy RT Dorsey et al. Transl Cancer Res 2013

6 Supposed mechanism Photoelectric effect predominant for low kv Can produce energetic secondary electrons Dose enhancement Less effect in MV range 2 nd electrons Auger electrons Mesbahi et al. Rep Pract Oncol Radiother 2010 X-ray Fluorescence photon Reactive Oxygen Species (ROS) Long range effect and Short range effect X-ray

7 Can we do the same with protons? 2 MV terminal voltage (4 MeV H +, 6 MeV He 2+, 12 MeV C 5+ ) Multi-ions DC beam: DC ion sources and 100 V ripple on 2 MV. Originally designed for material analysis SINIX ion source (H -, C - ) Low energy magnet Duoplasmotron ion source (He+) TiH 2 + (C) He + + Cs H +, He ++, C 5+ H -, C -, He - Electrostatic lenses Lithium electron adder canal (He + > He - ) Faraday cup & BPM Low energy acceleration Power supply amplification +HV High energy acceleration Stripper canal Electrostatic lenses Accelerating tube RBS analysis chambre ERD/RBS analy chambre & Irradiation sta UHV analys chambre Implantatio chamber

8 Low energy protons We play with LET Broad beam: Statistical hit of cells 1,0 0,8 0,6 0,4 0,2 Débit de dose (Gy/min) 0, X (mm) Y (mm) 8 10

9 Uptake in cancer cells Blue area : Nucleus staining Red area : Actin staining Green dots : gold nanoparticles and aggregates A431 cells (Epidermoid carcinoma) at UNamur 0.5 pg/cell

10 Surviving Fraction Amplification ratio Evidence with protons Epidermoid carcinoma with low energy protons 1 H +, E=1.3 MeV LET=25 KeV/µm 0,45 0,40 Difference of fitted data (AuNPs_5 nm) Difference of fitted data (AuNPs_10 nm) 0,35 0,30 0,1 0,25 0,20 0,15 0,10 0,01 A 431 A 431+ AuNPs (5nm, 0.05 mg/ml, 24h incub.) A 431+ AuNPs (10 nm, 0.05 mg/ml, 24h incub.) Dose (Gy) See poster of Dr. Li 0,05 0,00 0,0 0,5 1,0 1,5 2,0 2,5 3,0 Dose (Gy) /!\ Generally, less pronounced effect

11 Mechanisms of action with protons 2 nd electrons Yes but shorter range than X-ray induced Auger electrons Short range X-ray Fluorescence photon Unlikely for low energies But probably relevant for SOBP Charged particle Localized effect compared to X-rays What is the dose increase? Is there a significant physical effect? Reactive Oxygen Species (ROS) Localized effect

12 Geant4 single nanoparticle irradiation Geant4 toolkit to track particles in matter Input data based on in vitro experiments Nanoscale (nanoparticle in water) and microscale (cell) approaches Core + coating H 2 O Various diameters Various materials 1.3 or 4 MeV protons H 2 O Gold core H 2 O Secondary electron scoring Inside NP At NP surface Linear energy transfer (LET) profile

13 Gold or titanium core 1.3 MeV protons Auger transition in titanium Low energies lost in bulk Auger for lower Z

14 Number of emitted electrons Yield of secondary electrons at NP surface compared to water (1.3 MeV protons) Material Pt Au Au Auger off Ta Hf Zr Ti Ti Auger off water Yield Mean E (kev) Size effect Gold 5 nm 10 nm 25 nm 50 nm Yield per incident proton at NP surface Proportion trapped in bulk

15 LET profile 5 nm gold nanoparticles irradiated by 1.3 MeV protons Low energy secondaries from coating Au Au + PEG Au + PEG (auger off) Water equivalent Local LET in the vicinity of gold nanoparticles! Does this explain the increase in cell killing?

16 Nanoscale approach Pt, Au best emitters Also Ti because of Auger emission Large NP high selfabsorption but still more efficient at 50 nm Coating low energy contribution Geant4 limitations (Auger cascade and low energy cross sections)

17 Cell geometry Nanoscale (nanoparticle in water) and microscale (cell) approaches Yellow: interactions X-Ray emission 2 nd e- emission Scattering Proton, 1.3 MeV

18 GEANT4 single cell irradiation Required dose (Gy) Proton only (Gy) SD Proton + 10 nm gold NP (Gy) SD pg/cell gold nanoparticles (white random spots) Total surface area = 3.89 µm² (vs 322 um² for the cell) 3Gy: 240 protons, and only 2.85 protons hit GNP 1 % proton in GNP for a 50 % increase in cell death?

19 So how does it work? Local increase in LET with the presence of gold nanoparticles But marginal physical effect: a few are actually irradiated! Biological or chemical phenomena? Local increase of reactive oxygen species? (see talk of S. Penninckx) Thermal effect? Local increase in temperature near a proton track Proton 1,3 MeV Proton 1,3 MeV + gold nanoparticles 35 C 260 C Melting temperature of DNA 85 C In cytoplasm? Integrity of proteins is compromised

20 UNamur irradiation facility Low energy particle accelerator is a convenient tool Bottow up approach that supports clinical science. Helps to understand and evaluate new clinical procotols Our radiobiology platform is available for experiments. stephane.lucas@unamur.be anne-catherine.heuskin@unamur.be

21 Acknowledgments