1. May 01RWS Development of Nanodosimetry for Biomedical Applications Project Goals and Current Status

2. May 01RWS Project Participants Loma Linda University (LLU) (Rad. Medicine) Reinhard Schulte Vladimir Bashkirov George Coutrakon Pete Koss Weizmann Institute of Science (WIS) (Rad. Detection Physics Lab.) University of California at San Diego (UCSD) (Radiobiology) Amos BreskinGuy Garty Rachel ChechikItzhak Orion Sergei Shchemelinin John F. Ward Jamie Milligan Joe Aguilera University of California Santa Cruz (UCSD) (Santa Cruz Institute of Particle Physics) Abe SeidenPatrick Spradlin Hartmut SadrozinskiBrian Keeney Wilko Kroeger

3. May 01RWS What is Nanodosimetry? A new experimental technique that measures energy deposition by ionizing radiation in wall-less low-pressure gas volumes equivalent to tissue-equivalent volumes of nanometer size

4. May 01RWS delta rays Ionization event (formation of water radicals) Light damage- reparable Clustered damage- irreparable Radiation Damage to the DNA Water radicals attack the DNA The mean diffusion distance of OH radicals before they react is only 2-3 nm OH e-e- Primary particle track

5. May 01RWS What do we want to know? how many where To better understand DNA damage we want to know how many ionization events occurred and where did they occur. Problem: How can we measure the formation of ions with nanometer precision? Using conventional techniques - impossible We can only measure ion formation with millimer resolution If we had millimeter DNA - no problem. Solution: Solution: We measure ionization patterns in low-pressure gas

6. May 01RWS Project Goals Establishment of a nanodosimetric gas model to simulate ionizations in DNA and associated water Plasmid-based DNA model to measure DNA damage Develop models to correlate nanodosimetric spectra with DNA damage

7. May 01RWS Project Schedule YEAR 1 YEAR 2 YEAR 3 Ion counting nanodosimetry (proof of principle) Plasmid assays ND fabrication (2 versions) ND characterization ND improvements 2 D particle tracking 2001 2000 1999 1998 YEAR 4 3D tracking system SV mapping ND spectra MC simulation

8. May 01RWS ion counter E 1 (pulsed) E 2 (strong) primary particle detector ion primary charged particle  electron low pressure gas vacuum z x y E 3 (weak) electron Gas based electron multiplier low pressure gas Single-Charge Counting Dosimetry

9. May 01RWS Current Status of the Ion Counting ND Principle proven (1998) Two prototype of NDs have been built: –LLUMC ND adapted to the proton synchrotron beam line –WIS ND adapted to the Pelletron beam line 2-D particle selection implemented Data Acquisition System –first version successfully implemented –new version under development

10. May 01RWS Prototype Nanodosimeter

11. May 01RWS Sensitive Volume Mapping The sensitive volume of the ND is defined by the relative ion collection efficiency map

12. May 01RWS ND Ion Cluster Spectra A primary particle event is followed by an ion trail registered by the ion counter (electron multiplier) For low-LET irradiation, most events are empty microseconds millivolts 0123 -5 0 -20 Event with 6 ions

13. May 01RWS ND Ion Cluster Spectra Ion cluster spectra depend on particle type and energy as well as position of the primary particle track The average cluster size increases with increasing LET

14. May 01RWS Radiobiological Model Plasmid (pHAZE) –Irradiation of thin film of plasmid DNA in aqueous solution –Three structural forms: superhelical (no damage) open circle (single strand break) linear (double strand break) –Separation by agarose gel electrophoresis –Fluorescent staining and dedicated imaging system

15. May 01RWS Correlation between Nanodosimetry and Radiobiology

16. May 01RWS ND Data Acquisition (non-position sensitive) In the prototype ND all primary particles can contribute to the ion cluster size spectra The position of the primary particles is undefined

17. May 01RWS ND Data Acquisition (particle-position sensitive) In this (newer) version the primary beam is “imaged” by a MWPC Only particles that pass a narrow collimator in front of the rear scintillator/PMT are selected for analysis

18. May 01RWS The Goal: 3-D Position- and Energy-Sensitive Particle Tracking System interface board Y X primary particle