Boron neutron capture therapy: A new era in radiotherapy

To the Editor: Boron neutron capture therapy (BNCT) comprises a type of radiotherapy that fuses heavy-ion cancer therapy with the delivery of boron-containing drugs, based on the principle that compounds with the boron-10 isotope (¹⁰B) are absorbed into the body, rapidly gather in tumor cells, and then neutron beams generated from a reactor or an accelerator can be used to irradiate the tumor. Compared with conventional radiotherapy, BNCT can more effectively kill tumor cells and cause less damage to normal cells, making it one of the most advanced cancer treatments currently available.

Mechanism of tumor cell death induced by BNCT: At present, the biological mechanism of BNCT is not completely clear. Neutron-mediated destruction of tumor cells is related to unrepaired DNA double-strand breaks (DSBs) and antiangiogenesis. BNCT can induce tumor cell necrosis and apoptosis by regulating B-cell lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX), releasing cytochrome c, increasing tumor necrosis factor receptor levels, and activating the expression of caspase-3, 7, 8, and 9. BNCT can also improve the immunogenicity of the tumor microenvironment. The combination of Bacillus Calmette-Guerin (BCG) and BNCT might act as an “anti-tumor vaccine” in which BNCT would trigger the process of tumor antigen generation and BCG would promote antigen presentation in an inflammatory microenvironment against the primary tumor and its metastasis. The mechanism of tumor cell death and immune response induced by BNCT is shown in Figure 1.

Figure 1.

The mechanism of tumor cell death and immune response induced by BNCT in mice. BAX: BCL2-associated X protein; BCL-2: B-cell lymphoma 2; BNCT: Boron neutron capture therapy; Cas: Caspase; CDK1: Cyclin-dependent kinase 1; CTL: Cytotoxic T lymphocytes; Cyto-C: Cytochrome C; DNA: Deoxyribonucleic acid; G1: First gap; G2: Second gap; He: Helium; IFN-γ: Interferon-γ; IL-2: Interleukin-2; Li: Lithium; M: Mitosis; PBMC: Peripheral blood mononuclear cell; S: Synthesis; Th: T helper cell type.

Accelerator-based neutron sources for BNCT: The quality of the neutron beam is a key factor for clinical BNCT. Considering P-boronophenylalanine’s (BPA’s) metabolism in cancer cells and patient comfort, neutron irradiation must be completed within 1 h. A clinical study by Avijit Goswami showed that a neutron fluence of 10¹²/cm² is the critical requirement for the success of BNCT.^[1] Before the 2010s, research reactors were almost the only ones that could meet the neutron flux requirement in BNCT and had made great contributions throughout the development of this field. At present, only two reactors (one in Chinese Taiwan, and one in Kyoto, Japan) are still carrying out clinical BNCT.

Compared with a reactor, accelerator-based BNCT (AB-BNCT) has many advantages. The parameters of the accelerator can be adjusted according to the clinical treatment, whereas the output of a reactor is often difficult to control. The volume of an accelerator is also significantly smaller than a reactor, which can reduce maintenance costs. Moreover, the higher safety of an accelerator makes it possible to construct epithermal neutron sources in medical facilities. Accelerator-based neutron sources as a reactor replacement for clinical BNCT are strongly considered around the world. In 2020, Neu-Cure, developed by Sumitomo Heavy Industries (Tokyo, Japan), was registered as a radiotherapy device in Japan. In Chinese mainland, two AB-BNCT centers in Xiamen and Dongguan have been established. Xiamen Humanity Hospital has began the clinical trials, while the Tenth Affiliated Hospital of Southern Medical University/Dongguan People’s Hospital has completed the installation of accelerator-based neutron source and is about to enter a new stage of clinical research.

To meet the requirements for clinical treatment, an accelerator-based neutron source must accelerate high-current particles ranging from several milliamperes to several tens of milliamperes, and its power can reach several tens of kilowatt. At present, beryllium or lithium are commonly used as conversion media to generate neutrons for AB-BNCT devices. When using lithium as the conversion target, the neutrons produced by ⁷Li(p, n)⁷Be reaction are relatively low, which requires a larger average proton current (10–30 mA) to bombard the lithium target than the beryllium target. The low melting point (182°C) and thermal conductivity (84 W·m⁻¹·K⁻¹) of lithium meant that an advanced cooling technology is crucial for timely heat dissipation from lithium-based neutron source. However, compared to beryllium-based accelerators, the lithium-based accelerator has significant advantages in low incident proton energy and small size. In addition, the neutrons produced from ⁷Li(p, n)⁷Be reaction are only a few hundred kiloelectron volt, which helps lower the size of the epithermal neutron moderator and shield, contributing to reducing the construction cost of an AB-BNCT facility. The proton beam of 20 mA and 2.8 MeV has been produced by linear accelerator to interact with a 0.2-mm thick lithium target to produce a neutron beam that meets clinical requirements.

Development of boron-containing drugs: In recent years, scientists have studied boron-containing drugs to improve their tumor specificity and uptake of ¹⁰B, which depends mainly on the concentration ratio of ¹⁰B between tumor and normal tissue (T/N) and between tumor and blood (T/B). BPA and sodium borocaptate (BSH) are the most widely used agents used to deliver boron to treat cancer using neutron capture therapy, research has mainly focused on optimizing their delivery, developing a new generation of boron-containing drugs, and combining BNCT with other treatments.

The blood–brain barrier (BBB) is the main obstacle to the diffusion of boron carriers in the brain; therefore, changing the route of administration can improve BSH and BPA uptake by brain tumors significantly. In an F98 glioma model, hyperosmotic mannitol induced BBB disruption (BBB-D) after intra-arterial administration via the internal carotid artery, resulting in a prolonged median survival time (MST) and an increase in the cure rate. Compared with intravenous administration, cerebrospinal fluid administration could enhance the concentration range of BPA in tumor tissues and increase the ¹⁰B concentration in the T/N. Thus, delivery optimization can significantly enhance the treatment efficacy of BNCT.

Various derivatives of BPA and BSH could be used as potential boron-delivery drugs, including boronated nucleic acids, protein components, polymers, monoclonal antibodies, and chelate complexes. Kalot et al^[2] constructed a fluorescent aza-BODIPY/¹⁰B-BSH compound, which could vectorize and image the ¹⁰B-BSH in the tumor region, thereby increasing BNCT’s theranostic potential. There have been few studies on derivatives of BPA. Boronophenylalanine-fructose (BPA-f) could significantly improve the water solubility of BPA and increase the drug concentration in tumor cells. The MST in F98 glioma-bearing rats receiving boronophenylalanine-amide alkyl dodecaborate (BADB) combined BPA was longer than that in the rats receiving BPA alone.

Cancer combination therapies involving radiotherapy and chemotherapy have been widely used to improve the efficacy of treatment and prevent cancer recurrence. Researchers have combined chemotherapy with BNCT. Boron-10-rich nanosheets (BNNSs) were constructed as a dual-function delivery system, comprising a BNCT-activated targeted boron 10 delivery system and a doxorubicin (DOX) delivery carrier for chemotherapy. The combination of radiotherapy and chemotherapy showed a significant effect in inhibiting the growth of triple-negative breast cancer.^[3] Chen et al^[4] combined DOX and carboborane (CB) into DOX-CB, constructed a novel nanoliposome multifunctional delivery system termed DOX-CB@lipo-pDNA-iRGD, then blocked the CD47-SIRPαmacrophage immune checkpoint pathway using the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 system, and combined immunotherapy with BNCT. DOX-CB@lipo-pDNA-iRGD markedly increased the survival and improved the prognosis of tumor-bearing mice compared with BSH alone.^[4] In addition, low-dose of γ-radiation could increase the boron ratio of T/N and T/B and increase the efficacy of BNCT in an animal model of oral squamous cell carcinoma.

BNCT comprises targeted radiation therapy and can be used to treat infiltrating, recurrent, and metastatic tumors, such as recurrent head and neck tumors, gliomas, meningiomas, melanoma, and other cancers. In a Japanese phase I trial of the combination of ¹⁰B-boronophenylalanine (SPM-011) and BNCT in patients with unresectable head and neck cancer, 500 mg/kg SPM-011 (L-BPA) was administered to nine subjects, of which six received 10 Gy-equivalent and three received 12 Gy-equivalent as a mucosal dose. The results showed that 12 Gy-Eq is a safe dose. Then, a phase II clinical study (JHN002) for AB-BNCT was carried out to test its efficacy in treating head and neck tumors for the first time. Neutron irradiation after intravenous injection of ¹⁰B was administered to eight patients suffering from recurrent squamous cell carcinoma (R-SCC) and 13 patients suffering from recurrent/locally advanced nonsquamous cell carcinoma (R/LA-nSCC). Among all the patients, the objective remission rate was 71%. In patients with R-SCC and R/LA-nSCC, the complete remission/partial remission rates were 50%/25% and 8%/62%, and the 2-year overall survival rates were 58% and 100%, respectively.^[5] AB-BNCT presents some advantages compared with chemotherapy radiotherapy/immunotherapy to treat recurrent head and neck tumors. Based on the results of the accelerator-based BNCT study, BNCT is an approved treatment in Japan for locally recurrent unresectable head and neck tumors.

However, BNCT still has some shortcomings, such as high technical requirements for neutron sources and the boron concentration, making it difficult to popularize and apply in clinical practice. The first Chinese AB-BNCT equipment was established in Xiamen Humanity Hospital in 2019. So far, 14 patients have been treated. In addition, many BNCT projects are under construction and planning in China. Our country’s independently developed radio frequency quadrupole AB-BNCT equipment for the treatment of recurrent head and neck cancer, glioma, melanoma, and meningioma will be installed in our hospital soon. In the future, research into new boron drugs and promoters is required, as is the optimization of drug delivery methods in vitro and in vivo, the improvement of tumor targeting, and the concentration of boron drugs in tumors. Prospective randomized clinical trials should be carried out to observe the clinical effect of the treatment of malignant tumors with BNCT. In addition, BNCT could be combined with other therapeutic methods, including photon radiotherapy, chemotherapy, targeted therapy, and immunotherapy, with the aim of improving the efficacy of BNCT in treating malignancies.

Funding

This study was supported by grants from the Guangdong Basic and Applied Basic Research Fund (Guangdong-Dongguan Joint Fund; No. 2023B1515120072), the Dongguan Social Science and Technology Development Project (No. 20231800900382), the National Clinical Key Specialty Cultivation Project (No. Z202303), and the Open Fund of the China Spallation Neutron Source Songshan Lake Science City (No. KFKT2023A02).

Conflicts of interest

None.