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Boron Neutron Capture Therapy - perspectives for development in Bulgaria

Boron Neutron Capture Therapy - perspectives for development in Bulgaria. E. Borisova, L. Avramov , Ml. Mitev* Institute of Electronics, Bulgarian Academy of Sciences 72, Tsarigradsko chaussee blvd., Sofia 1784, Bulgaria *Institute for Nuclear Research and Nuclear Energy, BAS

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Boron Neutron Capture Therapy - perspectives for development in Bulgaria

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  1. Boron Neutron Capture Therapy - perspectives for development in Bulgaria E. Borisova, L. Avramov, Ml. Mitev* Institute of Electronics, Bulgarian Academy of Sciences 72, Tsarigradsko chaussee blvd., Sofia 1784, Bulgaria *Institute for Nuclear Research and Nuclear Energy, BAS 72, Tsarigradsko chaussee blvd., Sofia 1784, Bulgaria

  2. Cancer therapy Requirements • Selective destroy of cancer cells • Without/Minimal damaging of normal cells • High efficiency- most of the cancer cells should be destroyed, either by the treatment itself (necrosis) or with the help from the body's immune system (apoptosis) Today’s standard treatments • Surgery • Radiation therapy • Chemotherapy New cancer therapies • Photodynamic therapy – PDT • Boron neutron capture therapy – BNCT • Immunotherapy Successfully cured many kinds of cancers, but still many treatment failures High selectivity!

  3. Incident epithermal neutrons Thermal neutrons α Eα=1,47 MeV γ Eγ=0,48 MeV 10B 11*B t =10-12 sec 7Li E7Li=0,84 MeV Air Tissue BNCT-principles BNCTis a form of cancer therapy which uses a boron-containing compound that preferentially concentrates in tumor sites. The neutrons irradiated interact with the boron in the tumor to cause the boron atom to split into an alpha particle and lithium nucleus. Both of these particles have a very short range (about one cellular diameter) and cause significant damage to the cell in which it is contained.

  4. MechanismofBNCT binary treatment 10B drug 7Li 10B a 7Li neutrons a 7Li a 7Li a 7Li a 7Li a Thermal Neutrons no therapeutical effect, when applied alone But can be very effective when applied together

  5. BNCT – history • 1936 G.L.Locher (USA) proposes neutron capture reactions should • be applied to radiation therapy • 1940 (Farr) mouse sarcomas/boric acid/thermal neutrons • 1941 (Zahl) proposed higher energy neutron to treat deep-seated tumours • 1951-61 (USA) First trials of BNCT – 96% 10B-Borax • sodium pentaborate • p-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

  6. Present status 1. 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 2007 10.HANORA, S. Korea 2007 In total …. over 360 patients Hence, a grand total of almost 1000 patients worldwide have received BNCT …

  7. Neutron 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

  8. Research Reactor IRT Refurbishment • reactor of thermal power 200 kW • LEU fuel U-235 fuel • six vertical experimental channels • seven horizontal experimental channels • maximal fast neutron flux : 3.1012 n/cm2s • maximal thermal flux: 8.1012 n/cm2s Strategy for Sustainable Utilization • Education and training of students, physicists and engineers in the field of nuclear science and nuclear energy • Implementation of applied methods and research • Development and preservation of nuclear science, skills, and knowledge

  9. National BNCT network Project DO-02-58/2008 “Development of infrastructure for neutron therapy in Bulgaria” • Medical University in Sofia • Institute of Electronics of the BAS • Institute of Experimental Pathology and Parasitology of the BAS • Medical University in Varna • National Centre of Radiobiology and Radiation Protection Activities for NCT development for cancer treatment Building of NCT facility Modeling of NCT Beam Tube on IRT in Sofia NCT Scientific Information SystemNCT Scientific Infrastructure Building

  10. BNCT – disadvantages • First medical experimental trials in the 50-60’s failed to show good evidence of therapeutic efficacy. Why? 1) thermal neutrons are attenuated rapidly in tissue due to absorption and scattering, and their useful depth of penetration for NCT therapy is limited to 3-4 cm. This means that only superficial tumors would be destroyed by the 10B capture reaction. 2) The boron compounds that were used were freely diffusible, low molecular weight substances that did not achieve selective localization in the tumor. Those which did had high blood values, and this explains why so much radiation was delivered to adjacent normal brain.

  11. How to improve BNCT? • Using photosensitizers : • Fluorescence detection – • for diagnostic purposes • Selective accumulation – for PDT &BNCT therapy High tumor selectivity

  12. Accumulation in the target tissue (tumor) MechanismofPDT binary treatment Drug administration Optical fibers tumor Laser source 405, 630, 660, 700 nm

  13. Principles of PD and PDT Molecule energy Radicals: O2- H2O2 HOCl NO ONOO - NO2 HO 1O2 Relaxation S1 T1 O2* Light absorption Therapy Diagnosis Fluorescence O2 S0

  14. Sensitizers in photodiagnosis MM-second week of growth Human bladder mucosa in vivo: Visualisation of a flat multicentric carcinoma in situ which is hardly visible in the white light mode. MM-fourth week of growth Cutaneous Malignant Melanoma* * Own results ** Lund Laser Center – MEDPHOT Atlas- http://medphot.jrc.it/medphot/atlas/html/bladder_-_fluorescence_4.html

  15. PDT necrosis cell membrane Ca2+ mitochondrion ER cytochrome C DNA cleavage nucleus caspase activation protein cleavage CELL DEATH PDT-targets and mechanisms

  16. Sensitizers and radiation therapy • High tumor-targeting ability of sensitizers • Non-chelated Gd3+ ions are toxic in vivo as a results of their rapid hydrolisis to Gd(OH)3, which deposits in liver and bones • For Gd(III)-texaphyrin is known to react with hydrated electrons and to allow the production of cytotoxic hydroxyl radicals, both arising from the radiolysis of water presented in tissues; • After one electron reduction Gd(III)-texaphyrin reacts with molecular oxygen to generate superoxide anions. • Detectable by MRI – as a result of their paramagnetic nature – Gd-porphyrin (XcytrinTM). Under investigations

  17. Expected outcome • Further optimization of the beam tube for specific IRT, Sofia geometry conditions: Filter/moderator, Collimator with extender, Shutter design (1MW) in collaboration with MIT team • NCT infrastructure building • Multidisciplinary team enforcing • Strengthening international collaboration HUMAN, SOCIAL AND ECONOMICAL RESULTS DUE TO THE NCT FOR MANY PATIENTS FROM BALKAN REGION ARE EXPECTED WE HAVE ALL POTENTIALS TO CREATE A FACILITY WITH PROPERTIES PROVIDEDAT THE BEST FACILITIES ALREADY EXISTED/APPLIED

  18. Thank you very much for the attention! AcknowledgementsThis 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”

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