**1. Introduction**

### **1.1. Boron neutron capture therapy: historical account**

In 1932 in the UK, Chadwick discovered neutrons, and for his contribution, he was awarded in 1935 with the Nobel Prize in Physics [1]. One year later in the USA, Gordon Locher introduced the concept of boron neutron capture therapy (BNCT) [2]. He hypothesized that if boron could be selectively concentrated in a tumoral tissue and then exposed to a neutrons

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

beam, a higher radiation dose to the tumor relative to surrounding normal cells would result. A mere 2 years later, Goldhaber, Hall, and Kruger performed the first radiobiological studies using boric acid and slow neutrons in a murine tumoral model [3]. However, the first clinical trials against human brain tumors (glioblastoma multiforme (GBM)) that used BNCT could not be initiated until 1951 at the Brookhaven National Laboratory in collaboration with the Massachusetts General Hospital and the Massachusetts Institute of Technology (MIT) [4, 5]. In this case, ten patients were treated with borax (disodium tetraborate decahydrate, Na2 B4 O7 ·10H2 O; **Figure 1**) and thermal neutrons without much success. While there were no serious side effects of BNCT in the patients, the large doses of borax (10B-enriched) infused 200 mg/kg, inducing slight toxicity symptoms. In order to improve this, a second approach was developed comprising nine glioma patients but now with a less toxic compound, sodium pentaborate (NaB5 O8 ; **Figure 1**) in combination with D-glucose. Unlike the first one, a higher dose of 10B was used, and a higher fluency of incident thermal neutron was applied [6]. Unfortunately, again, serious side effects such as radio-dermatoses of the scalp and deep ulcerations were observed [6, 7]. Simultaneously, in 1963, Sweet and co-workers, from the MIT, treated 18 patients using boron-rich disodium decahydrodecaborate (Na2 B10H10; **Figure 1**) [8], which was considered to be less toxic and with the ability to deposit more boron atoms per cell. Symptoms of brain necrosis in patients undergoing BNCT were again observed [9]. Due to these disappointing events, the USA halted the progress of research on BNCT in 1961.

The probability that a nuclide captures a neutron is measured by the neutron capture cross section, σth, having 10B a value of σth = 3838 barns [15]. However, other abundant endogenous nuclei

14N(n,p)14C. However, the σth of these nuclei is smaller than the value for 10B, i.e., σth,1H = 0.332 and σth,14N = 1.82 barns, and the amount of radiation produced by these nuclear reactions is

On the other hand, for brain tumor such as GBM, usually higher energy epithermal neutron beams which have a greater depth penetration being thermal neutrons unable to act on tumors located below the tissue surface because of scattering effects have been used. Epithermal neutrons do not suffer from the disadvantages of H-recoil processes and, consequently, allow capture reactions to occur at some distance within the tissue; then, epithermal neutrons are progressively slowed into thermal neutrons through heat-releasing interactions with the hydrogen

lesser than the produced by the particle and recoiling nucleus in the case of boron [15].

atom and constituents of biological system, that do not cause damage to the tissue [16].

the tumor tissue, i.e., at least 20 μg 10B/g tumor, corresponding to about 109

In order for BNCT to be successful, the 10B-loaded agent must completely fulfill some overriding conditions, namely, (a) selective uptake by tumor tissue relative to normal tissue (preferably accumulating within specific tumoral cell substructure) with ideal tumor:normal tissues and tumor:blood ratios of 3:1 and 5:1, respectively, and (b) appropriate amount of 10B delivered to

**Figure 2.** The two parallel nuclear fission reactions that occur upon capture of a slow (thermal) neutron by a 10B nucleus.

H(n,γ)2

Medicinal Chemistry of Boron-Bearing Compounds for BNCT-Glioma Treatment: Current Challenges…

H and 14N, could also capture neutrons yielding after

H, and a proton in the second one,

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207

atoms of 10B/cell.

present in the healthy tissue, such as 1

nuclear reactions of a gamma ray in the first case, 1

**Figure 1.** First and current available boron-based drugs for BNCT.

On the other hand, in 1968 at Hitachi training reactor, the Japanese neurosurgeon Hiroshi Hatanaka, who in previous years had worked with Sweet in Boston, began treating patients with high-grade malignant gliomas using disodium mercaptoundecahydro-*closo*-dodecaborate (Na2 B12H11SH, named as BSH; **Figure 1**) which originally had been synthesized by Soloway in 1967 [10]. The results reported by Hatanaka and co-workers were extraordinary with a 5-year survival rate of 58% [11–13].

From the 1990s to the present day with the development of new boron compounds and the improvement in radiation source, the boron neutron capture therapy has been expanded to several centers worldwide, among them in the USA at Brookhaven and Cambridge, in the Netherlands at high flux reactor in collaboration with the Department of Radiotherapy of the University of Essen in Germany, in Finland at FiR-1 Otaniemi reactor, in Sweden at R2–R0 reactor, in the Czech Republic at LVR-15 reactor, in Italy at TRIGA reactor, in Japan at Kyoto University Research Reactor Institute, in Argentina at RA-6 and RA-3 reactors, and in Taiwan at THOR reactor, just to name a few [14].

### **1.2. Boron neutron capture therapy: principles and general requirements**

BNCT is considered as a rationale and promising binary therapy modality for treatment of several cancers in particular malignant gliomas. The cell-killing effect of BNCT is based on the nuclear reaction 10B(n,α)<sup>7</sup> Li (**Figure 2**) that occurs when the nuclide 10B, which is a nonradioactive constituent of natural elemental boron (approximately 20% abundance), is irradiated with neutrons of the appropriate energy, thermal neutrons. The nuclear reaction yields excited boron-11 (11B\*) that after instantaneous nuclear fission produces two high-linear energy transfer entities, i.e., α-particle (<sup>4</sup> He2+) and recoiling lithium-7 nucleus (<sup>7</sup> Li3+). Because of the very short track length of these heavy particles (<10 μm; roughly one cell diameter), radiation damage is confined to those cells loaded with 10B.

The probability that a nuclide captures a neutron is measured by the neutron capture cross section, σth, having 10B a value of σth = 3838 barns [15]. However, other abundant endogenous nuclei present in the healthy tissue, such as 1 H and 14N, could also capture neutrons yielding after nuclear reactions of a gamma ray in the first case, 1 H(n,γ)2 H, and a proton in the second one, 14N(n,p)14C. However, the σth of these nuclei is smaller than the value for 10B, i.e., σth,1H = 0.332 and σth,14N = 1.82 barns, and the amount of radiation produced by these nuclear reactions is lesser than the produced by the particle and recoiling nucleus in the case of boron [15].

beam, a higher radiation dose to the tumor relative to surrounding normal cells would result. A mere 2 years later, Goldhaber, Hall, and Kruger performed the first radiobiological studies using boric acid and slow neutrons in a murine tumoral model [3]. However, the first clinical trials against human brain tumors (glioblastoma multiforme (GBM)) that used BNCT could not be initiated until 1951 at the Brookhaven National Laboratory in collaboration with the Massachusetts General Hospital and the Massachusetts Institute of Technology (MIT) [4, 5]. In this case, ten patients were treated with borax (disodium tetraborate decahydrate,

serious side effects of BNCT in the patients, the large doses of borax (10B-enriched) infused 200 mg/kg, inducing slight toxicity symptoms. In order to improve this, a second approach was developed comprising nine glioma patients but now with a less toxic compound, sodium

dose of 10B was used, and a higher fluency of incident thermal neutron was applied [6]. Unfortunately, again, serious side effects such as radio-dermatoses of the scalp and deep ulcerations were observed [6, 7]. Simultaneously, in 1963, Sweet and co-workers, from the MIT,

which was considered to be less toxic and with the ability to deposit more boron atoms per cell. Symptoms of brain necrosis in patients undergoing BNCT were again observed [9]. Due to these disappointing events, the USA halted the progress of research on BNCT in 1961.

On the other hand, in 1968 at Hitachi training reactor, the Japanese neurosurgeon Hiroshi Hatanaka, who in previous years had worked with Sweet in Boston, began treating patients with high-grade malignant gliomas using disodium mercaptoundecahydro-*closo*-dodecab-

Soloway in 1967 [10]. The results reported by Hatanaka and co-workers were extraordinary

From the 1990s to the present day with the development of new boron compounds and the improvement in radiation source, the boron neutron capture therapy has been expanded to several centers worldwide, among them in the USA at Brookhaven and Cambridge, in the Netherlands at high flux reactor in collaboration with the Department of Radiotherapy of the University of Essen in Germany, in Finland at FiR-1 Otaniemi reactor, in Sweden at R2–R0 reactor, in the Czech Republic at LVR-15 reactor, in Italy at TRIGA reactor, in Japan at Kyoto University Research Reactor Institute, in Argentina at RA-6 and RA-3 reactors, and in Taiwan

BNCT is considered as a rationale and promising binary therapy modality for treatment of several cancers in particular malignant gliomas. The cell-killing effect of BNCT is based on

dioactive constituent of natural elemental boron (approximately 20% abundance), is irradiated with neutrons of the appropriate energy, thermal neutrons. The nuclear reaction yields excited boron-11 (11B\*) that after instantaneous nuclear fission produces two high-linear

of the very short track length of these heavy particles (<10 μm; roughly one cell diameter),

Li (**Figure 2**) that occurs when the nuclide 10B, which is a nonra-

He2+) and recoiling lithium-7 nucleus (<sup>7</sup>

B12H11SH, named as BSH; **Figure 1**) which originally had been synthesized by

treated 18 patients using boron-rich disodium decahydrodecaborate (Na2

**1.2. Boron neutron capture therapy: principles and general requirements**

O; **Figure 1**) and thermal neutrons without much success. While there were no

; **Figure 1**) in combination with D-glucose. Unlike the first one, a higher

B10H10; **Figure 1**) [8],

Li3+). Because

Na2 B4 O7 ·10H2

pentaborate (NaB5

orate (Na2

O8

206 Glioma - Contemporary Diagnostic and Therapeutic Approaches

with a 5-year survival rate of 58% [11–13].

at THOR reactor, just to name a few [14].

energy transfer entities, i.e., α-particle (<sup>4</sup>

radiation damage is confined to those cells loaded with 10B.

the nuclear reaction 10B(n,α)<sup>7</sup>

On the other hand, for brain tumor such as GBM, usually higher energy epithermal neutron beams which have a greater depth penetration being thermal neutrons unable to act on tumors located below the tissue surface because of scattering effects have been used. Epithermal neutrons do not suffer from the disadvantages of H-recoil processes and, consequently, allow capture reactions to occur at some distance within the tissue; then, epithermal neutrons are progressively slowed into thermal neutrons through heat-releasing interactions with the hydrogen atom and constituents of biological system, that do not cause damage to the tissue [16].

In order for BNCT to be successful, the 10B-loaded agent must completely fulfill some overriding conditions, namely, (a) selective uptake by tumor tissue relative to normal tissue (preferably accumulating within specific tumoral cell substructure) with ideal tumor:normal tissues and tumor:blood ratios of 3:1 and 5:1, respectively, and (b) appropriate amount of 10B delivered to the tumor tissue, i.e., at least 20 μg 10B/g tumor, corresponding to about 109 atoms of 10B/cell.

**Figure 2.** The two parallel nuclear fission reactions that occur upon capture of a slow (thermal) neutron by a 10B nucleus.

However, this amount could be lower if the boron delivery system is concentrated in or near the cell nucleus; (c) retention of 10B in tumor during the BNCT process; (d) rapid clearance from blood and healthy tissues; (e) and adequate lipophilicity especially for glioma treatment where the drug should be able to cross blood-brain barrier (BBB) [17]. Furthermore, like any drug in medicinal chemistry, the 10B-loaded agent must meet the following requirements: (f) absence of systemic toxicity, (g) chemical and metabolic stability, and (h) appropriate water solubility.

efficacy and the delivery into the glioma [20]. Medicinal chemistry on BSH, structural modifi-

Medicinal Chemistry of Boron-Bearing Compounds for BNCT-Glioma Treatment: Current Challenges…

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Nowadays, L-BPA (**Figure 3**) is the standard therapeutic drug used in BNCT [21–23]. Since the L-amino acid transport system is highly expressed in tumor cells compared with normal cells in most organs including the brain, some natural amino acid boron derivatives have been studied [24]. L-BPA has very limited water solubility (1.6 g/L), and searching to circumvent this problem, the standard strategy used for clinical BNCT treatment, it is as a soluble fructose complex, known as L-BPA-F (**Figure 3**), which leads to a pharmaceutical product with favorable biodistribution in human GBM, ratios tumor:blood of 3–4:1 [25], low toxicity, and good capability to cross BBB. Other two strategies include (a) the transformation into the corresponding hydrochloride salt and (b) the esterification of the boronic acid moiety with 1,2- and 1,3-diol producing 1,3,2-dioxaborolanes or 1,3,2-dioxaborinanes, respectively, which is then easily hydrolysable in an aqueous environment (**Figure 3**) [26, 27]. On the other hand, L-BPA is actively transported across the tumor cell membrane, by the L-amino acid transporter system. It is highly expressed in tumor cells, including the brain, compared with normal tissues and can be stimulated by the previous accumulation of the L-DOPA resulting in a substratecoupled antiport (exchange) mechanism [28]. At this point, L-BPA is considered to be a better

cations, has also been done (see below) seeking better biological behavior.

**2. Medicinal chemistry of boron-bearing compounds for BNCT**

*2.2.1. Implications for drug discovery: structural features of closo-carboranes and* 

*metallacarboranes. How do they influence on the drug-like properties?*

chemistry field are the icosahedral dicarba-*closo*-dodecaborane (C2

From a medicinal chemistry point of view, different strategies have been studied in order to identify new and more selective molecules to glioma cells, with adequate ability to cross the BBB, with higher tumor concentration in the path of the neutron beam and drug-like properties. The third-generation products, which potentially may accumulate into glioma for its structural analogy to some biomolecules, could be classified [15] in (a) macromolecular species and (b) low molecular weight molecules. In reference to the first group, we could mention monoclonal and bispecific antibodies, epidermal growth factor, and encapsulating agents such as boron-containing nanovehicles (liposomes). Here, we will discuss compounds belonging to the second group, like polyhedral boron cluster derivatives, boronic acid derivatives, and other boron-containing small molecules (e.g., oxaborolanes, dioxaborolanes, and

The most known and commonly used class of polyhedral boron compounds in the medicinal

to as carboranes which exist in three isomeric forms named with respect to the positioning of the two CH vertices (**Figure 4**): 1,2- or *ortho*- (**1**); 1,7- or *meta*- (**2**); and 1,12- or *para*-carborane (**3**); to a lesser extent, their mono-anionic derivatives resulting from the loss of a B vertex, commonly

B10H12) commonly referred

B delivery agent than BSH.

azaboro-heterocycles, among others).

**2.2. Polyhedral boron clusters**

**2.1. General**

### **1.3. Boron neutron capture therapy: current therapeutic agents**

After the first efforts, during the 1940s and 1950s (see Section 1.1.), the lack of selectivity and low boron tumor accumulation observed for the simplest boron salts (**Figure 1**) used until the moment prevented their application in BNCT clinical trials. However, around the 1960s, the first studies of the two compounds currently in clinical began, both 10B-enriched, the polyhedral borane BSH (**Figure 1**) and L-4-dihydroxyborylphenylalanine, known as L-boronophenylalanine (L-BPA; **Figure 3**) [18], which could be accumulated into desired tissues for its structural analogy to some biomolecules.

Due to BSH is a small hydrophilic molecule (**Figure 1**), it does not cross the intact BBB. It only penetrates into the brain passively when the BBB is disrupted [10], as it is observed in the GBM. Although BSH has been applied for the treatment of GBM in infusions with no toxic effects, the efficacy has been limited due to low observed tumor:brain (3:1) and tumor:blood (0.9–2.5:1) ratios [19]. The main structural advantage of BSH compared to L-BPA is that BSH contains 12 times more B per molecule yielding a higher number of events after neutron capture than in L-BPA. BSH has been studied in different therapeutic schedules, combined or not with other small molecules, like L-BPA, or vehicles looking for the improvement of the

**Figure 3.** (A) Currently, available boronic acid for treatment of GBM trough BNCT. (B) L-BPA-F complex. (C) Esterification of L-BPA with ethylene glycol.

efficacy and the delivery into the glioma [20]. Medicinal chemistry on BSH, structural modifications, has also been done (see below) seeking better biological behavior.

Nowadays, L-BPA (**Figure 3**) is the standard therapeutic drug used in BNCT [21–23]. Since the L-amino acid transport system is highly expressed in tumor cells compared with normal cells in most organs including the brain, some natural amino acid boron derivatives have been studied [24]. L-BPA has very limited water solubility (1.6 g/L), and searching to circumvent this problem, the standard strategy used for clinical BNCT treatment, it is as a soluble fructose complex, known as L-BPA-F (**Figure 3**), which leads to a pharmaceutical product with favorable biodistribution in human GBM, ratios tumor:blood of 3–4:1 [25], low toxicity, and good capability to cross BBB. Other two strategies include (a) the transformation into the corresponding hydrochloride salt and (b) the esterification of the boronic acid moiety with 1,2- and 1,3-diol producing 1,3,2-dioxaborolanes or 1,3,2-dioxaborinanes, respectively, which is then easily hydrolysable in an aqueous environment (**Figure 3**) [26, 27]. On the other hand, L-BPA is actively transported across the tumor cell membrane, by the L-amino acid transporter system. It is highly expressed in tumor cells, including the brain, compared with normal tissues and can be stimulated by the previous accumulation of the L-DOPA resulting in a substratecoupled antiport (exchange) mechanism [28]. At this point, L-BPA is considered to be a better B delivery agent than BSH.
