Boron Neutron Capture Therapy and Boron Delivery Agents: History
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Subjects: Oncology | Medicine, Research & Experimental
Contributor:
Xiang Cheng
,
Fanfan Li
,
Lizhen Liang

Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (10B) nuclei that have entered tumor cells to produce highly linear energy transfer (LET) alpha particles and recoil 7Li nuclei (10B [n, α] 7Li). The development of boron delivery agents has ushered in a new opportunity with the improvement of synthetic techniques and the increased understanding of the biochemical properties of groups.

  • boron delivery agents
  • boron neutron capture therapy (BNCT)
  • thermal neutron

1. Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a radiotherapy modality based on nuclear capture and fission reactions, which theoretically combines the advantages of “biological targeting” and “heavy ion radiotherapy”. The basic principle is that a boron-containing drug is injected into the patient, the boron compound accumulates in the tumor cells, and the tumor area is then irradiated with a neutron beam. After the neutron is captured by 10B, it transforms into 11B and the unstable 11B decays rapidly and emits α particles (4He) and recoil atoms 7Li (including ground state and excited state) in a fission reaction called 10B (n, α) 7Li fission reaction. Among them, alpha particles produced by fission are the main source of the radiation effect in BNCT.
The microscopic neutron capture cross-section of the nuclide and the nature of the fission products are two key factors in ultimately determining which element to use for neutron capture therapy (NCT). The former accounts for the ability of the nuclei used for NCT to absorb neutrons, while the latter determines the effectiveness of radiation in killing cancer cells. Referring to the data, 10B was found to be a qualified candidate for NCT with a neutron capture cross section of 3838 barns [1]. Neutron capture occurs when the non-radioactive component 10B is irradiated by low-energy (0.025 eV) thermal neutrons or high-energy (10,000 eV) epithermal neutrons, resulting in a fission reaction [2], The reaction formula is: 10B + n → 7Li + 4He; the reaction can release α particles (4He) and excited state 7Li cores (6.3%, total energy of 2.79 MeV) or ground state 7Li cores (93.7%, total energy of 2.31 MeV). A 0.48 MeV gamma photon is generated in the process of returning from the excited state to the ground state. The fission-produced alpha particle (4He) is a high LET particle with an LET ranging from 50 to 230 keV/μm [3][4][5]. 4He can induce DNA double-strand breaks, which usually lead to cell cycle arrest, followed by mitotic cell death, apoptosis or necrosis, effectively eliminating the tumor cells [6]. Furthermore, the distance that alpha particles travel in tissue is typically 50 to 100 microns, about the diameter of a cell [7][8][9]. If boron-containing drugs can be effectively enriched in tumor cells, BNCT can generate a large radiation gradient between the tumor and normal tissue. When BNCT eliminates tumor cells, it does not damage the surrounding normal tissue. Radiation-induced damage to normal tissue can be controlled at safe dose levels [10][11][12].
BNCT requires that boron-containing drugs selectively deliver sufficient 10B to tumor tissue (20–50 μg 10B/g or 109 10B atoms/cell) [13] and avoid excessive boron uptake by normal tissues to maximize radiation efficacy and protect normal tissues. Therefore, boron-containing drugs need to possess the following characteristics: high uptake by tumor tissue (the boron concentration needed is >20 µg 10B/g tumor tissue) and low uptake by normal tissue; concentration ratios of tumor to normal (T/N) and tumor to blood (T/B) not lower than 3; fast clearance after treatment; low systemic toxicity; etc. [14].

2. Neutron Beams

One of the key factors in the success of BNCT is the nature of the neutron beam. To achieve the desired therapeutic effect of BNCT, the neutron flux at the tumor site needs to reach 1012 neutron/cm2 [10].
The tissue penetration of neutron beams is far less than that of traditional X-ray photons, which results in the inability to deliver sufficient neutron flux to deep tumors in vivo. This limits the application of BNCT to a certain extent. The peak flux of thermal neutron beams first applied to BNCT is at a depth of about 2–3 cm below the skin surface, and at a depth of 10 cm, the neutron flux decreases rapidly to about one-tenth of the peak. This makes it difficult to meet the treatment requirements for deep tumors.
In the mid- to late 1990s, researchers began to increase the penetration depth of neutrons. One of the improvements was to use epithermal neutron beams with higher energy than thermal neutron beams [15]. On 13 September 1994, the U.S. Food and Drug Administration (FDA) approved a dose-escalation clinical trial of BNCT using boron delivery agent BPA-F and epithermal neutron beams in Brookhaven Medical Research Reactor (BMMR). From 1994 to 2000, several clinical trials using epithermal neutrons were carried out at BMRR (USA), MIT (USA), High Flux Reactor (Netherlands) and FiR1 (Finland) [16]; Kawabata made the first attempt in Japan using epithermal neutrons in 2003 [15]. Epithermal neutrons achieved the desired effect, and their application enabled superficial tumors within 6–8 cm of the skin surface to be included in the reach of the neutron beam [3]. This improvement also changed the previous status whereby intracranial tumors could only be irradiated with neutrons in the craniotomy state. It opened the way for the clinical application of BNCT and also provided the possibility of receiving BNCT for patients who could not undergo surgery.
Before 2012, most of the neutron sources used in BNCT were experimental neutron devices based on nuclear reactor facilities. For safety reasons, the construction site of the nuclear reactor facilities are usually located away from densely populated areas. In some studies, patients needed to be injected with boron-containing drugs in a medical institution before being transferred to the reactor facility where neutron equipment for irradiation was located. At the beginning of 2009, the world's first accelerator-based BNCT clinical irradiation system was completed at Atomic Furnace Laboratory of Kyoto University, Japan. Cell and animal clinical experiments were carried out in 2011, and the system has been used for clinical treatment since 2012. By the end of the November 2014, 510 clinical exposures had been performed using the reactor-based system [13]. Around 2014, Sumitomo Heavy Industries (Japan), Hitachi (Japan), Mitsubishi (Japan) and Neutron Therapeutics (USA) built accelerator-based neutron sources that could be installed in hospitals and produce epithermal neutron beams. More accelerator-based BNCT devices are reported in America, Russia, Britain, Italy, Israel and Argentina.
Accelerator-based neutron source facilities have many advantages over reactors. The output of the reactor is usually not easy to control, while the accelerator can allow researchers to adjust the parameters of the neutron beam according to needs. The volume of the accelerator equipment is significantly smaller than that of a reactor, which can reduce the maintenance costs of equipment; on the other hand, the higher safety of the accelerator guarantees the possibility to be built in medical facilities. Accelerator-based devices are likely to be the inevitable trend of BNCT in the next few decades.
In addition to directly enhancing the penetration ability of neutrons, researchers are also starting from other angles to enhance the penetration depth. For example, reducing the attenuation of neutrons in tissues is also a feasible means. According to Sakurai, the penetration depth of neutrons can be increased by draining out the cerebrospinal fluid (CSF) in the tumor-removed cavity and injecting air through an Ommaya’s reservoir [17]. This method can reduce the attenuation of neutrons in the cerebrospinal fluid, which can increase the penetration depth of neutrons and improve the neutron flux of deep tumors [18]. Kawabata successfully treated several patients with malignant meningioma with this technique [19].
In addition to the development of a more penetrating neutron beam on the basis of the accelerator, in the future, neutron beams may be able to be irradiated into the cavity during minimal invasive surgery using a compact neutron-beam guiding device instead of penetrating the body. Deep-seated tumors could be treated, which could also increase the application range of BNCT.

3. Boron Delivery Agents

3.1. First-Generation Boron Delivery Agents

Neutrons were discovered in 1932 by Professor James Chadwick of Cavendish Laboratory at Cambridge University [20]. In 1936, Gordon Locher published a discussion on the biological effects and therapeutic possibilities of BNCT. He pointed out that if a sufficient amount of 10B accumulates in tumor cells and is exposed to thermal neutrons, the radiation dose received by tumor tissue would be much greater than that of normal tissue. This makes boron neutron capture a viable treatment for cancer [21]. Boron is the most effective atom in neutron capture therapy, but the development of boron drugs was limited by the technical conditions at that time. Only boric acid, borax and pentaborate were synthesized.
Kruger [22] and Zahl [23] reported BNCT-related animal experiments in 1940. The first clinical application of BNCT was performed at Brookhaven National Laboratory (BNL) in 1951, at the neutron facility of Brookhaven Medical Research Reactor (BMMR). However, due to the injection of the non-targeting boron compound, it could not be effectively enriched in tumor cells, resulting in a low ratio (<1) of the concentration of boron in tumor cells to that in normal cells and blood. Therefore, the killing effect on tumor cells was not ideal [24]. Several attempts have been made since then. From 1959 to 1961, several patients with intracranial tumors underwent BNCT at BMRR; during the same period, 17 patients with malignant gliomas underwent BNCT at the Massachusetts Institute of Technology (MIT) reactor [25]. The median survival time of these patients was only 87 days. These trials used different boron compounds and various surgical interventions, but the findings were unsatisfactory. Slatkin’s animal study showed that during neutron irradiation, the concentration of boric acid in the blood was three times higher than that in the brain parenchyma, that is, vascular endothelial cells absorbed more radiation from alpha particles and 7Li particles than brain parenchymal cells. Endothelial cell injury may be a major determinant of acute lethality in CNS radiation syndrome [26].
All clinical trials of BNCT in the United States were discontinued in 1961 based on serious adverse events. The key defect of the first-generation delivery agents represented by boronic acid was the lack of tumor targeting. Their concentrations in tumors are very low compared to normal tissue, and their accumulation in tumor cells is transient [24][26] and cannot be used as boron carrier in clinical settings.

3.2. Second-Generation Boron Delivery Agents

Around the 1960s, two boron compounds that later proved to be effective, boron phenylalanine (BPA) and boron card sodium (BSH), were first synthesized in 1958 and 1967, respectively. They are less toxic than first-generation boron compounds, have a longer duration of intratumoral enrichment and have a ratio of boron concentrations greater than 1 in T/N and T/B [11]. In 1968, Hatanaka began to try BNCT in Japan, using BSH as a boron delivery agent, and successfully treated many patients with high-grade glioblastoma (GBM). After long-term follow-up observation, the 5-year survival rate of his patients was 58%, and the 10-year survival rate was 29% [27].
Hatanaka’s and Soloway’s work in the field is in the spotlight [28][29]. Since the 1980s, with the improvement of neutron beams and the availability of second-generation boron compounds, especially after the successful purification of the levorotatory enantiomer of BPA (L-BPA) in 1980 [30], some countries in Europe and the United States have once again set off a research boom in BNCT. Finland conducted BNCT research using an FiR-1 reactor with the support of VTT Corporation [31]. The Coderre team in the United States used BPA to treat glioma tumor-bearing mice, and its therapeutic effect reached expectations f [32]. The birth of second-generation boron delivery agents laid the foundation for the clinical research of BNCT. So far, they have successfully treated more than 2000 patients with malignant tumors, and they are also the only two drugs that are currently allowed to be used in clinical practice.

3.3. Third-Generation Boron Delivery Agents

The development of boron delivery agents has ushered in a new opportunity with the improvement of synthetic techniques and the increased understanding of the biochemical properties of groups. In order to meet the needs of BNCT and broaden the clinical application of BNCT, many new boron delivery agents have emerged.
There are many types of third-generation drugs, including boronated amino acids, polypeptides [33][34][35][36], protein [2]; boronated porphyrins, folate receptors, boronated DNA intercalators, carboranyl nucleosides [37][38][39][40], Borated Epidermal Growth Factor (EGF) [41][42], boronated MAb to epidermal growth factor receptor (EGFR) [43]; Liposome Boron Delivery Agent [44][45][46], transferrin liposomes [47]; boron-containing nanomaterials [48][49], BSH polymeric micelles [50], etc. And also including the modification of BPA and BSH [14][51][52][53]. The effectiveness of BNCT depends on the intracellular localization of 10B [6][54].
With random distribution within the cell, it is estimated that about 109 atoms of 10B are required to kill tumor cells. Boron delivery agents that specifically target DNA are expected to significantly reduce this amount [13]. Therefore, delivery agents that can localize boron in the nucleus, such as boronated nucleotides or their precursors, may be ideal agents for the selective delivery of 10B into cancer cells. This precise targeting capability is expected to reduce the dose of boron drugs required for therapy, thereby reducing potential drug toxicity and the neutron dose required for irradiation.

This entry is adapted from the peer-reviewed paper 10.3390/curroncol29100622

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