May 01 RWS

Development of Nanodosimetry for

Biomedical Applications

Project Goals and Current Status

May 01 RWS

Project ParticipantsLoma 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 Breskin Guy Garty

Rachel Chechik Itzhak Orion

Sergei Shchemelinin

John F. Ward

Jamie Milligan

Joe Aguilera

University of California Santa Cruz (UCSD) (Santa Cruz Institute of Particle Physics)

Abe Seiden Patrick Spradlin

Hartmut Sadrozinski Brian Keeney

Wilko Kroeger

May 01 RWS

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

May 01 RWS

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-

Primary particle track

May 01 RWS

What do we want to know?What do we want to know?To better understand DNA damage we want to know how manyhow many ionization events occurred and wherewhere did they occur.

Problem:Problem:How can we measure the formation of ions with nanometer precision?

Using conventional techniques - Using conventional techniques - impossibleimpossibleWe 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

May 01 RWS

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

May 01 RWS

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 43D tracking system

SV mapping

ND spectra

MC simulation

May 01 RWS

ion

coun

ter

E1

(pulsed

)

E2

(strong)

prim

ary

part

icle

dete

ctor

ion

prim

ary

char

ged

part

icle

elec

tron

low

pre

ssur

e ga

sva

cuum

z

x

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E3

(weak)

elec

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Gas

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low

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gas

Sin

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Ch

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May 01 RWS

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

May 01 RWS

Prototype Nanodosimeter

Scintillator/PMT

Ionization cell

Ion counter

Pump 1

Pump 2

Source

Side view Front view

May 01 RWS

Sensitive Volume Mapping

The sensitive volume of the ND is defined by the relative ion collection efficiency map

May 01 RWS

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

mil

livo

lts

0 1 2 3

-50

-20

Event with 6 ions

May 01 RWS

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

May 01 RWS

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

May 01 RWS

Correlation between Nanodosimetry and

Radiobiology

Nanodosimeter

0 minutes 15 minutes 30 minutes 60 minutes 120 minutes

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dsb

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00 1 22 3 44 5 66 7 88 9 1010111212131414151616171818192020%0%2%4%6%8

%10%12%14%16

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Re

lativ

e fr

eq

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Cluster size

protons 4 MeV 5 MeV

Rad

iatio

n

Plasmid Sample

GelElectrophoresis

Incubation withBase ExcisionEnzymes

Frequency oflesions of differentcomplexities

IonizationCluster Spectra

May 01 RWS

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

Accelerator Gate Signal

PCI Bus

Preamplifiers

Discriminators

Time-to-DigitConverter

+ HV

Plastic ScintillatorsDegrader

PMTs

Primary Particle

Prim

aryP

article Trigger

Ionization Cell

Ion Counter

Data Acquisition PC

May 01 RWS

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

1mm collimator

PMT

SV

Mylar window

MWPC

May 01 RWS

The Goal: 3-D Position- and Energy-Sensitive Particle

Tracking System

interface boardinterface board

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XX

primary particleprimary particle