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Boron and Gadolinium Neutron Capture Therapy
Chapter
1
Introduction
Malignancy is a life-threatening condition in which tumor cells are of a
highly invasive character and penetrate normal organs and exhibit an
obstinate resistance against cancer therapy. Glioblastoma multiforme
(GBM) in the brain, undifferentiated carcinoma of the thyroid gland,
small cell lung cancer, and malignant melanoma are typically malignant
and their five-year survival rates are very low, 5–10%. It is an earnest
wish to control them in human being. However, malignant tumors are
highly invasive, they easily metastasize to the lymph nodes and other
organs at a very early stage. As a rule, a malignant brain tumor (e.g. GBM)
does not invade extracranially, but it invades throughout the brain at an
early stage. Generally, malignancies are treated by multidisciplinary
modalities, such as extirpation + radiation + chemotherapy as shown in
Fig. 1.1. As for radiation therapy, malignant tumors are resistant to photon therapies, such as X-ray and γ-ray, thus high linear energy transfer
(LET) radiation such as heavy ionizing particles and neutron capture
therapy must be employed.
Neutron capture therapy (NCT) is a binary cancer treatment in which
a cytotoxic event is triggered when an atom, placed in a cancer cell,
absorbs a low energy, thermal, neutron. It is a seemingly ideal form of
therapy, in that it kills cancer cells while sparing healthy cells.
Although many of the references cited in this book are quite recent,
the basic concept of neutron capture therapy was first proposed in 1936
by Gordon L. Locher1 when he formulated his binary concept of treating
1
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Boron and Gadolinium Neutron Capture Therapy
Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment
Figure 1.1
The treatment strategy for malignancies.
cancer: enough knowledge of the remarkable behavior of neutrons has
been accumulated through physical research to enable the prediction of
certain biological effects, and to see, in a general way at least, certain
therapeutic potentialities of this new kind of corpuscular radiation. In
particular, there exist the possibilities of introducing small quantities
of strong neutron absorbers into the regions where it is desired to liberate ionization energy (a simple illustration would be the injection
of a soluble, nontoxic compound of boron, lithium, gadolinium, or
gold into a superficial cancer, followed by bombardment with slow
neutrons.
This remarkable approach to cancer treatment was proposed shortly
after the discovery of the neutron. It not only outlines the general
approach but also gives the two elements, boron and gadolinium, which
are currently studied as NCT agents. These two elements are unusual in
that several of their isotopes have very high abilities to absorb thermal
neutrons. The probability that a particular isotope will absorb a thermal
neutron is given by its nuclear capture cross section, σth, measured in
barns (b = 10−24 cm2). This should not be taken as a measure of physical
size, but rather as a measure of the probability of a nucleus absorbing a
neutron. In general the capture cross section of a nucleus increases as
the velocity of the bombarding neutron decreases; slow neutrons spend
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Boron and Gadolinium Neutron Capture Therapy
Introduction
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Figure 1.2 Change in the neutron capture cross section with the energy of
the neutrons.
more time around a nucleus and hence are more likely to be captured.
Figure 1.2 shows the change in cross section as a function of neutron
speed.
In the low-energy region (thermal neutrons) the cross section varies
as 1/v (v = speed of the neutron), this is the “1/v region” and the cross
section is large. This is followed by a region of resonance peaks where
the cross sections rise and fall sharply, depending on whether the energy
of the neutron closely matches the discrete quantum levels of the
nucleus. The fast neutron region, where the cross sections are very
small, follows this. In NCT, one is interested in the region of thermal
neutrons.
Boron-10, has an unusually high capture cross section of 3838 b,
while the isotopes 155Gd and 157Gd have even larger ones of 60,900 b and
255,000 b, respectively, for thermal neutrons. These cross sections are
orders of magnitude higher than those of the elements that constitute the
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Boron and Gadolinium Neutron Capture Therapy
Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment
Table 1.1 Thermal neutron capture cross sections of common biological tissue.
Nuclide
1
H
C
14
N
16
O
23
Na
24
Mg
12
Thermal
Neutron Capture
Cross Section
sth[b]
1 barn =
10–24 cm2
Weight % in
Mammalian
Tissue
0.333
0.0035
1.83
0.00019
0.43
0.0053
10
18
3
65
0.11
0.04
Nuclide
Thermal
Neutron Capture
Cross Section
sth[b]
1 barn =
10–24 cm2
Weight % in
Mammalian
Tissue
0.18
0.53
32.68
2.1
0.4
2.57
1.16
0.2
0.16
0.2
2.01
0.01
31
P
S
35
Cl
39
K
40
Ca
56
Fe
32
4
He2+(1.47 MeV) + 7Li3+ (0.84 MeV) + γ (0.48 ΜeV)
4
He2+ + 7Li3+ + 2.79 MeV
94%
10
B + nth
[11B]
6%
Scheme 1.1 Boron neutron capture reaction.
bulk of biological tissue (see Table 1.1.) The magnitude of these “cross
sections” depends on nuclear structure, for example, σth for 11B is only
5.5 × 10−3 b. This is significant in that natural abundant boron is only
about 20% 10B.
On absorption of a thermal neutron (E < 0.4 eV) by 10B, an excited
11
B is formed that almost immediately (∼10−12s) undergoes a fission reaction producing two high-energy heavy ions, 4He2+(α-particle) and 7Li3+,
and a low energy γ-ray (see Scheme 1.1).
The high kinetic energy 4He2+ and the 7Li3+ transfer their energies
over a very short distance, ~ 4–9 µm in biological tissue, this LET is of
the order of a cell diameter. Therefore, if sufficient compounds containing
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Boron and Gadolinium Neutron Capture Therapy
Introduction
157
Gd + nth
158
*Gd
158
5
Gd + γ + 7.9 MeV
internal conversion (IC) electrons
Auger−Coster−Kronig (ACK) electrons
Scheme 1.2 Gadolinium neutron capture reaction.
10
B can be preferentially absorbed in a cancer cell, and bombarded
with thermal neutrons, cell damage would be confined to that particular
cell, sparing neighboring healthy cells. This is the basis of all BNCT
treatments.
The gadolinium neutron capture (GdNC) reaction, 157Gd(n,γ)158∗Gd,
is more complex than that of boron, and it is not a fission reaction. Of
its seven stable isotopes, gadolinium has two isotopes that are of interest to NCT, 155Gd (σth = 55,000 b) and 157Gd (σth = 255,000 b). The
157
Gd has the highest thermal neutron capture cross section of all the
stable isotopes in the periodic table. The GdNC reaction initiates complex inner-shell transitions, as shown in Scheme 1.2, that generate
prompt γ emission displacing an inner core electron which, in turn,
induces internal-conversion (IC) electron emission and finally
Auger–Coster–Kronig (ACK) electron emission along with soft X-ray
and photon emissions.3–8 The low-LET γ-rays have an average energy of
2.2 MeV with a range of several centimeters. The IC electrons possess
average energies of around 45 eV, paired with a range of several millimeters in physiological tissue. Finally, the range of the very low
energy ACK electrons is only several nanometers in aqueous solutions.
Although low in absolute energy, the ultra-short range of the ACK electron energy deposition effectively makes the ACK radiation component
of the GdNC reaction a high-LET-type and is radiologically the most
relevant component of the GdNC.9. The ACK electrons provoke high
LET-type damage with a mean free path of 12.5 nm. Since this ionizing
radiation is limited to molecular dimensions, it is essential to place the
gadolinium atoms within the DNA helix to induce significant DNA
damage in cancer cells.
Both clinical and chemical studies related to BNCT have progressed
since the early 1950s. Boron compounds are easily incorporated in organic
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N
N
N
Gd
O
O
O
O
O
O
O
O
O
O
H
O
H
Figure 1.3
MRI contrast agent [Gd(DTPA)(H2O)]2− magnevist.
structures and their chemistry has been extensively investigated.10 On the
other hand, the toxicity of Gd3+ had prevented its use until the development
of suitable complexes of Gd3+, such as gadopentetate dimeglumine,
[Gd(DTPA)(H2O)]2− (see Fig. 1.3), and their use as magnetic resonance
imaging (MRI) contrast agents in 1988. As a consequence, there is much
more literature available on BNCT than there is on GdNCT.11