Boron Neutron Capture Boron Neutron Capture Therapy - perspectives Therapy - perspectives

for development for development

in Bulgariain Bulgaria E. Borisova, L. AvramovE. Borisova, L. Avramov, Ml. Mitev*, Ml. Mitev*

Institute of Electronics, Bulgarian Academy of SciencesInstitute of Electronics, Bulgarian Academy of Sciences

72, Tsarigradsko chaussee blvd., Sofia 1784, Bulgaria72, Tsarigradsko chaussee blvd., Sofia 1784, Bulgaria

*Institute for Nuclear Research and Nuclear Energy, BAS*Institute for Nuclear Research and Nuclear Energy, BAS

72, Tsarigradsko chaussee blvd., Sofia 1784, Bulgaria72, Tsarigradsko chaussee blvd., Sofia 1784, Bulgaria

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Cancer therapyCancer therapyRequirementsRequirements

Selective destroy of cancer cellsSelective destroy of cancer cells Without/Minimal damaging of normal cellsWithout/Minimal damaging of normal cells High efficiencyHigh efficiency - most- most of the cancer cells should be of the cancer cells should be

destroyed, either by the treatment itself destroyed, either by the treatment itself (necrosis) (necrosis) or with the help from the body's immune systemor with the help from the body's immune system (apoptosis)(apoptosis)

Today’s standard treatmentsToday’s standard treatments SurgerySurgery Radiation therapyRadiation therapy ChemotherapyChemotherapy

New cancer therapiesNew cancer therapies Photodynamic therapy – PDTPhotodynamic therapy – PDT BBoron neutron capture therapy oron neutron capture therapy – – BNCTBNCT ImmunotherapyImmunotherapy

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BNCT-principlesBNCT-principlesBNCTBNCT is a form of cancer therapy which uses a boron-is a form of cancer therapy which uses a boron-containing compound that preferentially concentrates containing compound that preferentially concentrates in tumor sites. The neutrons irradiated interact with the in tumor sites. The neutrons irradiated interact with the boron in the tumor to cause the boron atom to split into boron in the tumor to cause the boron atom to split into an alpha particle and lithium nucleus. Both of these an alpha particle and lithium nucleus. Both of these particles have a very short range (about one cellular particles have a very short range (about one cellular diameter) and cause significant damage to the cell in diameter) and cause significant damage to the cell in which it is contained.which it is contained.

TissueAir

Incident epithermal

neutrons

10B 11*B7Lit =10-12 sec

E7Li=0,84 MeV

Eα=1,47 MeVα

γEγ=0,48 MeV

Thermal neutrons

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10B drug

Thermal Thermal NeutronsNeutrons

no therapeutical effect, when applied aloneBut

can be very effective when applied together

MechanismMechanism ofof BNCT binary treatmentBNCT binary treatment

1010BB

neutronsneutrons

77LiLi

77LiLi

77LiLi

77LiLi

77LiLi

77LiLi

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BNCT – historyBNCT – history1936 G.L.Locher (USA) proposes neutron capture

reactions shouldbe applied to radiation therapy

1940 (Farr) mouse sarcomas/boric acid/thermal neutrons1941 (Zahl) proposed higher energy neutron to treat

deep-seated tumours1951-61 (USA) First trials of BNCT – 96% 10B-Borax

sodium pentaboratep-carboxy. deriv.

phenylboranic acid- effective failure - due to inefficient, non-discriminating boron containing drugs, use of poorly penetrating thermal neutron beams

1963–1980s Professor Hatanaka (Japan) – glioma patients+BSH – first more impressive results

1988 Professor Mishima – metastatic melanoma/BPA

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Present statusPresent status1. HFR Petten 1997 [26-glioblastoma, 4-melanoma]2. JRR-4 (JAERI) 1998 [>20, gliomas, meningiomas]3. KUR, Kyoto, Japan 1998 [>50 head and neck]3. VTT, Finland 1999 [>200, now head and neck]4. Rez, Czech Rep. 2000 [5, glioblastoma]5. Studsvik, Sweden 2001 [>40]6. MIT, USA 2002 [7]7. Pavia, Italy 2001 [2, extracorporeal liver]8. Bariloche, Argentina 2003 [6, skin melanoma]9. THOR, Taiwan 200710.HANORA, S. Korea 2007

In total …. over 360 patientsHence, a grand total of almost 1000 patients worldwide have received BNCT …

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Neutron sourcesNeutron sources

nuclear research reactors accelerators radioisotopes (in particular 252Cf)

Neutron beam requirements epithermal neutron flux 109 neutrons/cm2s

(at the therapy position) neutron energy ~ 1 eV to ~ 10.0 keV gamma dose rate 2х10-13 Gy/cm2

fast neutron dose rate 2х10-13 Gy/cm2

current:flux (J/) ratio > 0.8

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Research Reactor IRT Research Reactor IRT RefurbishmentRefurbishment

reactor of thermal power 200 kWreactor of thermal power 200 kW LEU fuel LEU fuel U-235 fuelU-235 fuel six vertical experimental channelssix vertical experimental channels seven horizontal experimental seven horizontal experimental

channelschannels maximal fast neutron flux : 3.maximal fast neutron flux : 3.101012 12

n/cmn/cm22ss maximal thermal flux: maximal thermal flux:

8.108.1012 12 n/cmn/cm22ss

Strategy for Sustainable Strategy for Sustainable UtilizationUtilization

Education and training of students, physicists and Education and training of students, physicists and engineers in the field of nuclear science and nuclear energyengineers in the field of nuclear science and nuclear energy

Implementation of applied methods and researchImplementation of applied methods and research Development and preservation of nuclear science, skills, Development and preservation of nuclear science, skills,

and knowledgeand knowledge

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National BNCT networkNational BNCT networkProject Project DO-02-DO-02-5858/2008 “Development of /2008 “Development of

infrastructure for neutron therapy in Bulgaria”infrastructure for neutron therapy in Bulgaria”

Medical University in Sofia Medical University in Sofia

Institute of Electronics of the BAS Institute of Electronics of the BAS

Institute of Experimental Pathology and Institute of Experimental Pathology and Parasitology of the BAS Parasitology of the BAS

Medical University in VarnaMedical University in Varna

National Centre of Radiobiology and Radiation National Centre of Radiobiology and Radiation ProtectionProtectionActivities for NCT development for cancer Activities for NCT development for cancer treatmenttreatment

Building of NCT facilityBuilding of NCT facilityModeling of NCT Beam Tube on IRT in SofiaModeling of NCT Beam Tube on IRT in Sofia

NCT Scientific Information SystemNCT Scientific Information System NCT Scientific Infrastructure BuildingNCT Scientific Infrastructure Building

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BNCT – disadvantagesBNCT – disadvantages First medical experimental First medical experimental trials trials in the 50-in the 50-

60’s 60’s failed to show failed to show goodgood evidence of evidence of therapeutic efficacy. therapeutic efficacy. Why?Why?

1) 1) thermal neutrons are attenuated rapidlythermal neutrons are attenuated rapidly in tissue due to absorption and scattering, in tissue due to absorption and scattering, and their and their useful depth of penetration for useful depth of penetration for NCT therapy is limited to 3-4 cmNCT therapy is limited to 3-4 cm. This . This means that only superficial tumors would be means that only superficial tumors would be destroyed by the destroyed by the 1010B capture reactionB capture reaction..2) 2) TThe boron compounds that were used he boron compounds that were used were freely diffusiblewere freely diffusible, low molecular weight , low molecular weight substances that did substances that did not achieve selective not achieve selective localization in the tumorlocalization in the tumor. Those which did . Those which did had high blood values, and this explains why had high blood values, and this explains why so much radiation was delivered to adjacent so much radiation was delivered to adjacent normal brainnormal brain..

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How to improve BNCT?How to improve BNCT?

Using photosensitizers :-Fluorescence detection – for diagnostic purposes-Selective accumulation – for PDT &BNCT therapy

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MechanismMechanism ofof PDT binary PDT binary treatmenttreatment

tumor

Drug administration

Accumulation in the target tissue (tumor)

Laser sourceLaser source

405, 630, 660, 700 nm

Optical fibers

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Principles of PD and Principles of PD and PDTPDT

Molecule

energy

Light absorptio

nFluorescen

ce

SS00

SS11

Relaxation

TT11

OO22

OO22**

Radicals:O2

-

H2O2

HOClNOONOO -

NO2

HO1O2

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SSensitizers ensitizers in in photodiagnosisphotodiagnosis

* Own results** Lund Laser Center – MEDPHOT Atlas- http://medphot.jrc.it/medphot/atlas/html/bladder_-_fluorescence_4.html

Cutaneous Malignant Melanoma*

Human bladder mucosa in vivo: Visualisation of a flat multicentric carcinoma in situ which is hardly visible in the white light mode.

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PDT-targets and mechanismsPDT-targets and mechanisms

ER

nucleus

mitochondrion

cell membranenecrosis

Ca2+

cytochrome C

caspase activation

DNA cleava

ge protein cleava

ge

CELL DEATH

PDT

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Sensitizers and radiation Sensitizers and radiation therapytherapy

High tumor-targeting ability of sensitizersHigh tumor-targeting ability of sensitizers Non-chelated GdNon-chelated Gd3+3+ ions are toxic in vivo as a ions are toxic in vivo as a

results of their rapid hydrolisis to Gd(OH)results of their rapid hydrolisis to Gd(OH)33, , which deposits in liver and boneswhich deposits in liver and bones

For Gd(III)-texaphyrin is known to react with For Gd(III)-texaphyrin is known to react with hydrated electrons and to allow the production hydrated electrons and to allow the production of cytotoxic hydroxyl radicals, both arising from of cytotoxic hydroxyl radicals, both arising from the radiolysis of water presented in tissues;the radiolysis of water presented in tissues;

After one electron reduction Gd(III)-texaphyrin After one electron reduction Gd(III)-texaphyrin reacts with molecular oxygen to generate reacts with molecular oxygen to generate superoxide anions. superoxide anions.

Detectable by MRI – as a result of their Detectable by MRI – as a result of their paramagnetic nature – Gd-porphyrin paramagnetic nature – Gd-porphyrin (Xcytrin(XcytrinTMTM).).

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Expected outcomeExpected outcome Further optimization of the beam tube for specific Further optimization of the beam tube for specific

IRT, Sofia geometry conditions: Filter/moderator, IRT, Sofia geometry conditions: Filter/moderator, Collimator with extender, Shutter design (1MW) in Collimator with extender, Shutter design (1MW) in collaboration with MIT teamcollaboration with MIT team

NCT infrastructure building NCT infrastructure building Multidisciplinary team enforcing Multidisciplinary team enforcing Strengthening international collaboration Strengthening international collaboration

HUMAN, SOCIAL AND ECONOMICAL RESULTS DUE HUMAN, SOCIAL AND ECONOMICAL RESULTS DUE TO THE NCT FOR MANY PATIENTS FROM BALKAN TO THE NCT FOR MANY PATIENTS FROM BALKAN REGION ARE EXPECTEDREGION ARE EXPECTED

WE HAVE ALL POTENTIALS TO CREATE WE HAVE ALL POTENTIALS TO CREATE A FACILITY WITH PROPERTIES PROVIDEDA FACILITY WITH PROPERTIES PROVIDEDAT THE BEST FACILITIES ALREADY AT THE BEST FACILITIES ALREADY EXISTED/APPLIEDEXISTED/APPLIED

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Thank you very much for Thank you very much for the attention!the attention!

AcknowledgementsAcknowledgementsThis work is supported by the

National Science Fund of Bulgaria - Ministry of Education, Youth and

Science under grant DO-02-58/2008 “Development of

infrastructure for neutron therapy in Bulgaria”