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

2. Cancer therapy Selective destroy of cancer cells
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. BNCT-principles α γ Tissue Air 10B 11*B 7Li
BNCT is 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.
Tissue
Air
Incident
epithermal
neutrons
10B
11*B
7Li
t =10-12 sec
E7Li=0,84 MeV
Eα=1,47 MeV α γ
Eγ=0,48 MeV
Thermal

4. Mechanism of BNCT binary treatment
10B drug
neutrons a
7Li
10B
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
(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 In total …. over 360 patients
1. HFR Petten [26-glioblastoma, 4-melanoma]
2. JRR-4 (JAERI) [>20, gliomas, meningiomas]
3. KUR, Kyoto, Japan 1998 [>50 head and neck]
3. VTT, Finland [>200, now head and neck]
4. Rez, Czech Rep [5, glioblastoma]
5. Studsvik, Sweden 2001 [>40]
6. MIT, USA [7]
7. Pavia, Italy [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 beam requirements
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 : n/cm2s
maximal thermal flux: 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 System NCT 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. High tumor selectivity
How to improve BNCT?
Using photosensitizers :
Fluorescence detection –
for diagnostic purposes
Selective accumulation – for PDT &BNCT therapy
High tumor selectivity

12. Mechanism of PDT binary treatment
Drug administration
Accumulation in the target tissue (tumor)
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-

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

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 PROVIDED AT THE BEST FACILITIES ALREADY EXISTED/APPLIED

18. Thank you very much for the attention!
Acknowledgements This 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”