Boron Neutron Capture Therapy: Current Status and Challenges

Abstract

Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (⁴He) and recoil lithium particles (⁷Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.

Introduction

The role of radiation therapy in the treatment of cancer is widely recognized, and radiation therapy is required in at least 50% of cancer patients (1). Although radiotherapy has long been considered a local treatment, it is likely to lead to serious complications, especially in patients with recurrent cancer, which will make the symptoms more complex and difficult to cure. With the development of biological and physical technologies, researchers have developed a number of new approaches that may be used to solve these problems. One of them is boron neutron capture therapy (BNCT), a technology based on boron nuclear reactions (Figure 1A). After being irradiated by neutrons, ¹⁰B becomes unstable ¹¹B, which continues to decay its energy and radiates α particles (⁴He) and ⁷Li recoil particles, releasing a large amount of energy and accompanied by a small amount of gamma rays during the reaction. The BNCT treatment process requires selectively boron accumulation of non-radioactive drugs in tumor cells, followed by the irradiation of local tissue with neutron beams, causing the release of large quantities of high-energy particles with nuclear fission to selectively kill the tumor cells in a narrow range (Figure 1B). The radiation radius of the reaction limits its scope of action, and tumor cells can be rapidly and selectively killed once boron is ingested without damaging the surrounding normal tissue (2, 3) (Figure 1C). BNCT has been studied in a variety of diseases, including glioblastoma multiforme (GBM), primary and recurrent head and neck cancer, lung cancer, liver cancer, and extramammary Paget’s disease (4, 5). Therefore, BNCT has very good development value and application prospects (Table 1 summarizes the clinical trials of BNCT in recent years). In fact, BNCT has been evaluated as an alternative treatment for a variety of cancers, including GBM, melanoma, and head and neck cancer in multiple phases I and II clinical trials. However, there are many factors against BNCT, such as cell selectivity of boron delivery agents, delivery mode, and irradiation depth of neutron beam and reactor, all of which involve the intersection of multiple technologies.

Figure 1

Clinical Investigations

Considering the factors affecting the application of BNCT, it is necessary to pay attention to the key issues at each stage of the design, such as the location and depth of the lesion, the absorption of the ¹⁰B delivery agent, the cycle and intensity of neutron beam irradiation, and the pharmacokinetics. Previously, Joensuu and Hideghéty et al. from the University of Helsinki have done detailed studies on the metabolism and toxicity of several boron delivery agents (6–8). The concentration and injection rate of para-boron-phenylalanine (BPA)-fructose (BPA-F) were controlled below 500 mg/kg/h, and a large number of relevant clinical data were obtained. These results suggest the feasibility of this therapy and provide valuable experience for further exploration. As we can see from Table 1, BNCT is still not widely used, restricted by insufficient experience in drug usage, difficulties in patient recruitment, lack of medical neutron sources, and other factors; this has resulted in relatively slow development and clinical implementation of BNCT. We will discuss these issues in detail in this review.

Compared with the traditional therapy, BNCT has the following advantages (9): a) the level of boron-containing drugs in tumor cells differs greatly from that in normal cells, leading to the content of ¹⁰B in tumor cells being higher than that in normal cells, so the damage to normal cells is less; b) radiotherapy requires oxygen to enhance the effect of biological radiation, but the aggressive proliferation of malignant tumor cells is very fast, which causes local hypoxia and reduces the therapeutic effect. Moreover, α particles and ⁷Li are not dependent on oxygen, so they have the same ability against tumor cells in oxygen-rich and hypoxic environments. c) Chemotherapy, γ knife, and radiotherapy have effects on tumor cells in the proliferative cycle (G1, S, G2, and M stages) but are not sensitive to G0 phase tumor cells. However, α particles and ⁷Li killer cells are independent of the cell cycle and can kill tumor cells at all phases. This review will introduce the research status of BNCT, the design and study of boron drugs, the results of clinical trials, and the therapeutic characteristics.

Based on previously published results (10–12), we focus on clinical trials over the past 20 years. Locher first elaborated the idea and principle of neutron capture therapy (NCT) in 1936 (13). The first clinical trial of BNCT was initiated by Farr and Sweet et al. in 1951. They used Brookhaven Graphite Research Reactor to treat GBM (14). In 1963, Sweet et al. used para-carboxylic phenylboric acid and Na₂B₁₀H₁₀ as boron delivery agents for BNCT treatment in glioma patients. Na₂B₁₀H₁₀ demonstrated better efficacy in the experiment, including lower toxicity and a higher ¹⁰B distribution ratio (tumor/blood) (15). By 1968, Hatanaka et al. showed a 5-year survival rate of 58% when they pretreated the patient’s tumor tissue with borocaptate sodium (BSH) (Na₂B₁₂H₁₁SH) and directly irradiated the surgically exposed intracranial tumor bed with a neutron beam, a very good result for that day (15–17). In 1987, Mishima and his colleagues first used BNCT in the treatment of malignant melanoma via BPA as a boron delivery agent. It was also the first attempt to use BNCT in the treatment of peripheral tumors outside the central nervous system.

Until the 1990s, BNCT research was intensive. Since then, several countries have suspended BNCT research, which has been linked to incidents in some nuclear reactions. After that, the work related to BNCT has focused on the pharmaceutical properties of boron delivery agents and animal experiments. However, in Taiwan Veterans General Hospital, clinical research related to BNCT on head and neck cancer was carried out in 2010 and 2013. They increased the dose to 500 mg/kg and supplemented it with superficial irradiation, which also achieved ideal effects. In recent years, The Third Xiangya Hospital of Central South University in China conducted a BNCT study involving 22 melanoma patients from 2013 to 2016. They used a specialized in-hospital neutron irradiator (IHNI) and continued to deliver BPA-F at a speed of 180 mg/kg/h. The results showed that within 24 months after the treatment with this therapy, the pigment plaque produced by the lesions in the affected area was significantly less. A small amount of residual can be identified as small pigmented plaque formed by the deposition of dead cells. The results of case analysis conducted about 9 months after treatment also indicated that these small pigmented plaques did not spread and did not invade deep cortical layers, causing metastasis and recurrence, which is a very exciting result (18). Here we can see that there is still a vast space for the development and clinical application of boron delivery agents.

Boron-containing compounds have been extensively studied in many areas including pharmaceutical chemistry and medicine. While the value of boron-containing compounds has long been recognized, there are still only a few boronated drugs to choose from. Carboranes are a class of organic compounds containing carbon, boron, and hydrogen. They are the most widely studied boron compounds in pharmaceutical chemistry. In addition, other boron-containing compounds are also of great concern, such as the perhydrodecaborate anion. BNCT has been used for cancer research for decades; before the full clinical potential of BNCT can be realized, there is a need to improve existing topical delivery agents (BPA/BSH) or develop some novel tumor-targeting boron delivery agents. Here we present the current clinical trials of boronated drugs (Table 2) and focus on the improvement and clinical significance of developed and improved boron-based bioactive compounds in the treatment of BNCT.

One advantage of BNCT over conventional radiotherapy is that its clinical efficacy depends largely on the high accumulation of ¹⁰B in tumor cells with minimal uptake of normal cells. This would allow the BNCT to target cancer cells for damage while protecting the surrounding normal tissue. Therefore, the development of boron delivery agents with high selectivity is one of the main directions in the development of BNCT. Based on clinical experience during the development of the BNCT, the researchers summarized a number of principles for evaluating the efficacy of the delivery agent. The five most important factors are as follows: each tumor cell contains more than 10⁹ (1.66 × 10⁻³ pmol) ¹⁰B atoms; the T/N (tumor/normal) and T/B (tumor/blood) concentration ratios of boron atom are greater than or equal to 3; the drug itself has low cytotoxicity; it can be quickly removed from normal tissues and blood but has a long time of stable retention in tumor cells; it is distributed in lipophilic and hydrophilic phases (amphiphilicity of delivery agents) in tissue, especially in brain tumors (2, 10, 44, 45). These principles guide the design, selection, and development of reagents for use in BNCT for subsequent in vitro and in vivo evaluations. According to the types of carriers, boron delivery agents could be divided into three types: boron-containing small molecules, boron-containing complexes, and boron-containing nanoparticles (2, 44, 46–49). Among these vectors, the most interesting development direction is targeted boron delivery agents, which usually bind boron-containing agents to various targeted molecules (such as nucleosides, peptides, proteins, porphyrins, or antibodies) of tumor cells. Another targeted boron delivery agent is the combination of boron-containing molecules and nanomaterials, which can take advantage of the enhanced permeability and retention (EPR) effects of nanomaterials as well as the active targeting effect mediated by grafted tumor-targeting ligands to transport boron-containing compounds into tumor cells (49).

Clinical Trials With Boron Delivery Agents

Boron Delivery Agents

BNCT is a novel method, which is still being tested, and its potential is clear, though it will have little impact on the mainstream of medicine. Chadwick discovered the neutron in 1932, and 4 years later, Locher proposed using the neutron capture reaction in cancer treatment (13). The first clinical trial of BNCT was not implemented until 1951 (14), and in 1961, about 40 patients were treated with BNCT in 10 years with varying degrees of results, but often with varying degrees of side effects (50), such as necrosis (51), edema, and refractory shock (52). These disappointing results led the BNCT study to stop in the United States. In 1968, Hatanaka conducted the BNCT trial in Japan, using the synthetic compound BSH as a boron delivery agent for treatment as intraoperative radiotherapy after tumor resection (53), where direct exposure of the tumor bed to a neutron beam reported encouraging results, with a 5-year overall survival (OS) rate of 58% in patients with grade 3 and 4 GBM (16, 17, 54). By 1987, Mishima et al. began treating superficial malignant melanoma with BPA. This section focuses on the relatively complete clinical trials of BNCT and related boron delivery agents, with details on GBM, head and neck cancer, and melanoma (39, 55).

Figure 2 shows a variety of modified small molecule boron agents, some of which have been in clinical trials for many years, while others are still under study. At present, only BPA (64) and BSH (53) have been applied in clinical trials, among which BSH is the first boron-containing compound in clinical application. Its advantage lies in its extremely high boron content; that is, each BSH molecule carries 12 ¹⁰B atoms, which is very helpful for the accumulation of ¹⁰B in tumor cells. This molecule was synthesized by Hatanaka et al. It was used to treat glioma in 1968 (39). In 1987, Mishima et al. first used BPA to treat malignant melanoma and found that it can selectively accumulate in tumor cells (55, 56). BPA is a phenylalanine analog, which is mainly transported to tumor cells through L-type amino acid transporter 1 (LAT-1) on the surface of the cell membrane, and this protein is overexpressed on the surface of malignant tumor cells. Hence BPA is also easier to accumulate in tumor cells. In clinical trials, BPA has a better affinity for tumor cells than BSH, and the emergence of BPA has also significantly accelerated the progress of research on targeted boron delivery agents.

Figure 2

BPA-F has better solubility than BPA; fructose is linked to BPA in the form of borate ester, resulting in improved solubility and biocompatibility of BPA. In addition, this combination promoted the more efficient distribution of BPA in the body and increased uptake by tumor cells. In 1994, BNCT was used for malignant intracranial glioma via BPA-F (65). Since then, BPA-F has been widely used in clinical trials in Japan, Sweden, Finland, China, and Taiwan to treat a variety of malignancies. Hattori et al. synthesized a series of derivatives of BSH (Figure 2) with low cytotoxicity and high lipophilicity and thus could be used as novel boron delivery agents in BNCT (61, 66). Compared to BPA alone, these delivery agents showed higher uptake and kill rates on cells (66). They found that the α,α-cycloalkyl amino acids, known as cis- or trans-ACBC, caused tumor cells to accumulate more ¹⁰B atoms than L-BPA and its short-chain lipid amino acid derivatives in several cell lines (C6, U81, and A172) expressing the L-type amino acid transporter (LAT) (61, 62). Al-Madhoun et al. analyzed the properties of 3-carboranyl thymidine analogs (3-CTA), including catalytic kinetic parameters, stability against other enzymes, n-octanol/water distribution coefficient, cytotoxic activity, intake of compounds, and retention time in various cell lines (57, 67). At last, they study the distribution of ¹⁰B atoms in rats with F98-glioma via N5-2OH (57). The results indicated that the level of ¹⁰B in glioma and normal brain tissue was 16.2 ± 2.3 and 2.2 μg/g, respectively. The concentration ratio of ¹⁰B in glioma and normal brain tissue was 8.5 (57, 68).

Miura et al. synthesized a series of complexed metallic porphyrins (60, 69–74). Cu(II) and Zn(II) porphyrins complex, also known as CuTCPH and ZnTCPH in Figure 2, are currently the most deeply studied porphyrin derivatives in vitro and in vivo (60). After injection of ZnTCPH or CuTCPH into mice, the distributions of ¹⁰B in different tissues were similar in mice carrying EMT-6, and the T/B and T/N ratios of ¹⁰B were larger (about 60:1 and 8:1, respectively). The tumor-bearing mice were injected with ZnTCPH fluorescence in the spleen, liver, and tumor. CuTCPH or ZnTCPB can also be used as a probe for tumor imaging via⁶⁷Cu-based single photon-emission CT (SPECT) or ⁶⁴Cu-based positron emission tomography (PET) (60).

Peptide transporter 1 (PepT1) is an oligopeptide transporter whose expression is increased in tumor cells. As a potential biomarker and tumor therapeutic target, PepT1 has attracted much attention (75, 76). Miyabe et al. proposed the selective delivery of boron to tumor cells via PepT1. They found that the dipeptide (BPA-Tyr and Tyr-BPA, Figure 2) formed by condensation of BPA and tyrosine could be ingested by ASPC-1 cells via the PepT1-mediated oligopeptide transport pathway; their T/B ratios of ¹⁰B were 2.00 ± 0.09 and 1.98 ± 0.05, respectively, 3 h after the drug was injected into AsPC-1-bearing mice. At 3 and 5 h after injection, the concentrations of ¹⁰B were 7.29 ± 0.31 and 6.48 ± 0.30 ppm, respectively (77).

Due to the ability of neuropeptide Y (NPY) to bind to the Y receptor with high affinity, the researchers developed a number of boron-containing NPY complexes as boron delivery agents based on this. [F⁷, P³⁴]-NPY showed a high affinity for the hY1 receptor (78), which led Ahrens et al. to develop ortho-carborane-containing NPY and a series of derivatives. The L-Lys modified by ortho-carboane was conjugated with [F⁷, P³⁴]-NPY to obtain [K⁴-Nε(Cpa)]-[F⁷, P³⁴]-NPY (Figure 2), which makes this molecule have extremely high affinity even at the nanomolar level and easy to be selectively ingested by tumor cells of the corresponding subtype (63).

In 2005, Wong et al. used cetuximab (IMC-C225, Erbitux) as an antibody against EGFR-mAbs for EGFR-positive recurrent colon cancer (79). Then, Wu et al. condensed cetuximab with the amino group of boronated polyamide dendrimer to obtain the bioconjugated BD-C225, which was absorbed by F98EGFR glioma and remained in the tumor cells for a long time, with undetectable ¹⁰B concentrations in blood and normal tissues (80, 81). They bonded cetuximab to Mal-PEG-Chol (maleimide-PEG-cholesterol liposomes) assembled with closo-carborane to enhance the drug uptake in F98EGFR gliomas by using the affinity of liposome to cell membrane structures (82). Yang et al. bonded modified cage boranes with polyamide amine dendrimer to form boronated dendrimer (BD). In addition, L8A4BD was re-bonded by L8A4 as a specific monoclonal antibody of EGFRVIII. The obtained molecule not only has the EGFRVIII targeting ability but also possesses the ¹⁰B to tumor cells and can also be used as an antibody–drug conjugate (83).

For boron delivery agents, targeting ability is the most critical factor. In addition to the targeting ability of the molecule to the tumor, the groups connected can improve the targeting ability of delivery agents to different cells. The most important criterion is the distribution of boron in the tumor and normal tissues. Besides, even in the case of more novel structural designs, the need to find molecules with potential effects via high-throughput screening ultimately requires strong coordination of synthetic chemistry. From the current development of boron drugs, researchers have found some boron-containing molecules as delivery agents, and there are fewer complications caused by the toxicity of the boron delivery agents in clinical trials. However, the targeting of molecules is not satisfactory at present, and there are still cases where the difference of boron concentration in tumor tissue is close to that in blood, skin, and mucosal tissue. Therefore, a future focus should be on chemical synthesis to improve target uptake of the molecules.

Glioblastoma

GBM is a common and aggressive malignant brain tumor. Currently, treatment for the disease is typically a multimodal combination of surgical resection, radiation, and chemotherapy. Conventional methods have a poor prognosis for high-grade gliomas, although radiation therapy is used to minimize tumor regression. Therefore, the inclusion of BNCT in combination therapy may be helpful for the cure of GBM. Table 3 summarizes relatively complete clinical studies of BNCT in GBM from 1999 to date.

Since 1999, Joensuu et al. have carried out clinical studies of BNCT for malignant glioma. In the first clinical trial, a total of 18 patients with GBM received BNCT based on a derivative of BPA. All patients had undergone surgery before BNCT, but none had undergone radiotherapy. The results showed that the treatment was generally well tolerated, with no patients dying in the months following and an overall 1-year survival rate of 61%. In another trial, none of the three patients with recurrent GBM died in the 3 months following BNCT (8). At the same time, Hideghéty et al. conducted clinical trials to study the uptake of the boron compound BSH in tumor and normal tissue. They measured levels of ¹⁰B in the blood, tumors, brain tissue, dura, muscle, skin, and bone of 13 patients who received the treatment. In the first group (10 patients), BSH was administered at 100 mg/kg; three patients in the second group received BSH at a concentration of 22.9 mg/kg. The results suggested that the mean boron concentration in tumor cells was 19.9 ± 9.1 ppm in the first group and 9.8 ± 3.3 ppm in the second group, and their T/B distribution ratios of ¹⁰B were 0.6 ± 0.2 and 0.9 ± 0.2, respectively. Among other tissues, dura absorption was the highest, and boron absorption was very low in the bone, cerebrospinal fluid, and especially the brain (brain/blood distribution ratios of ¹⁰B in both groups were 0.2 ± 0.02 and 0.4 ± 0.2). Therefore, BSH can be safely administered in the clinic at rates of 100 mg/kg/min. The study also speculated that boron concentration in the blood appeared to be a very reliable parameter for predicting boron concentration in other tissues.

Verbakel et al. conducted a dose-escalation research via BSH. The results indicated that the ratio of boron in blood to normal brain tissue ranged from 12 to 30, with very low concentrations in normal tissue. However, the concentration of ¹⁰B in normal superficial tissue was higher than that in normal brains, and the concentration was between 8 and 15 ppm. This result is consistent with previous studies that have shown that normal brain tissue absorbs boron delivery poorly. But the way they measured it, using the gamma rays of the nuclear reaction of boron, also suggested that the intensity of the gamma rays in the reaction could not be ignored, which is also a factor in tissue damage. Kawabata et al. reported the simultaneous use of sodium boroate and boron-phenylalanine as boron delivery agents, combined with fractional X-ray irradiation. The results showed that the median survival time (MST) for patients treated with BNCT was 15.6 months [95% (CI): 12.2–23.9]; compared with an MST of 10.3 months for patients treated with surgery and external beam radiation therapy (XRT) and chemotherapy (n = 27, MST was 10.3 months, 95% CI: 7.4–13.2), patients treated with BNCT had longer MST.

Melanoma

Melanoma is a malignant tumor produced by melanocytes, and so far, this remains a difficult cancer to treat with a poor prognosis. The usual treatment for cutaneous melanoma is surgical removal of the focus, sometimes lymph node dissection, and skin graft or flap repair (89–91). Table 4 summarizes relatively complete clinical studies of BNCT in melanoma from 2004 to date.

González et al. planned to enroll 30 melanoma patients for a clinical trial, and they reported the first results of BNCT for the treatment of melanoma. For the first patient, they administered BPA-F at 14 g/m² for more than 1.5 h, based on the area of the skin at the affected area (94, 95). Results showed that 19 of the 25 nodules were complete response (CR) within 4 weeks of BNCT treatment. After 8 weeks, 21 of the 25 nodules were CR, and 1 was partial response (PR). However, acute Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) grade 1 skin reaction was detected on the first day after treatment, but this reaction subsided after 8 weeks (92). Menéndez et al. performed BNCT on seven melanoma patients in Argentina. They injected BPA-F at doses of 14 g/m², with the maximum dose range of 16.5 to 24 Gy/m² for normal skin and 15.8 to 27.5 Gy/m² for normal tissue. The results indicated that the tumor/blood ratio of ¹⁰B was 1.7 to 2.5 (2 h 45 min for BPA-F injection), 2.4 to 4.1 (5 h for BPA-F injection), and 2.7 to 3.2 (10 h for BPA-F injection). The results suggested that 69.3% of the patients had a response, and the remaining 30.7% had no significant change during the postoperative and follow-up periods. At the same time, ulcerative radiation damage occurred in several patients, which was detected to be caused by high boron concentrations (40).

Yong et al. reported on a BNCT clinical trial in melanoma patients. They injected BPA-F at 350 mg/kg for more than 1.5 h and took samples before and after 1.5 h to calculate boron concentration ratios in different tissues. The results showed that the concentration ratios of T/N, T/B, and N/B were 1.30, 1.93, and 1.49 after 2 h of BPA-F injection, respectively. The concentration ratios of T/N, T/B, and N/B were 1.26, 2.51, and 1.99 after 3 h of BPA-F injection, respectively. After treatment, the lesion was significantly reduced, and no significant radiation damage was observed during follow-up (18). Hiratsuka et al. recently reported long-term clinical results in 8 patients using BPA as a boron delivery agent for BNCT. The experiment was conducted at the Kyoto University Research Reactor (KUR). Patients were irradiated with an epithermal neutron beam within the range of a therapeutic tumor dose and a tolerable skin dose. The results indicated that six of the eight patients had CR, while two patients showed a PR. Of the two patients, another presented with a PR after BNCT treatment and another palindromia after 6 years (96).

Head and Neck Cancers

Head and neck cancer is one of the most common cancers in the world and is difficult to cure, with high rates in Southeast Asia, Brazil, and central Europe (97, 98). In the past decade, we have learned that it is difficult to eradicate the lesion with a single treatment method, and the selective physical killing of tumor cells by BNCT is expected to be one of the combination methods for clinical treatment of head and neck cancer. BNCT for squamous cell carcinoma of head and neck (SCCHN) and recurrent head and neck carcinoma will be described in this section. Table 5 summarizes relatively complete clinical studies of BNCT in head and neck cancers from 2007 to date.

In 2007, Kankaanranta et al. reported BNCT effects in 12 patients with head and neck cancer. Results showed that 10 of the 12 patients had a PR (PR: 83%), and 2 patients had continued tumor growth. MST was 12.1 months (99). They then re-recruited 30 head and neck cancer patients (29 cancers and 1 sarcoma) for BNCT, 26 of whom received two treatments. The results suggested that of the 29 patients who participated in the efficacy evaluation, 22 patients had a PR (76%), and 6 patients had continued tumor growth. Median progression-free survival (MPFS) was 7.5 months (95% CI: 5.4–9.6 months), and 2-year PFS and OS rates were 20% and 30%, respectively (34). Therefore, it can be seen that BNCT can effectively treat local or recurrent head and neck cancer, and most patients can show a positive response to treatment. Therefore, BNCT can be appropriately considered as a clinical method with chemotherapy and radiotherapy.

Wittig et al. recruited six patients with head and neck cancer and used BSH and BPA as boron delivery agents. The results indicated that both BPA and BSH were better absorbed by the skin and mucous membranes. Therefore, for drug delivery in the patient, the delivery agents need to be overcome in the process of blood circulation by the skin and mucosal consumption. Wittig et al. also discussed the distribution of BSH and BPA in various viscera (32, 33). They suggested that BSH does not preferentially accumulate to liver metastases in patients with colorectal cancer. BPA is preferentially absorbed in liver metastases of colorectal adenocarcinoma to a degree sufficient for BNCT therapy. Therefore, BSH is not suitable as a ¹⁰B agent for the treatment of liver metastasis. However, the accumulation of BPA in liver metastases to a certain extent can be used to treat the liver via BNCT (41).

Wang et al. reported several trials for head and neck cancer. They chose 400 mg/kg of BPA as the administration method. The results indicated that four patients initially recruited showed different degrees of tumor tissue response after treatment, and patients had tolerance (35). In the second study of 17 patients, they also attempted to use BNCT in two sessions, and the results were satisfactory for both primary and recurrent head and neck cancer while maintaining a stable concentration of BPA in the blood (100). Six of the patients presented with a PR to the tumor, five with mucosal inflammation, one with laryngeal edema and carotid hemorrhage, and two with cranial neuropathy. Four patients showed CR (67%), and 2-year OS was 47% (36) in a recent clinical trial involving 17 patients. Wang et al. found that although some patients with BNCT can extend survival to more than 4 years, the inevitable failure factor is a local recurrence, which is difficult to control. At the same time, the complications associated with BNCT can be effectively controlled, which is a gratifying progress. In addition, they proposed that the combination of BNCT with image-guided photon therapy could reduce the recurrence rate and improve the therapeutic efficacy of BNCT (30).

Hirose et al. treated 8 patients with recurrent SCC (R-SCC) and 13 recurrent and locally advanced non-SCC (R/LA-nSCC) patients with cyclotron-based epithermal neutron source (C-BENS) and borofalan (¹⁰B) via BNCT. The objective was to evaluate the efficacy and safety of cyclotron-based BNCT combined with borofalan (¹⁰B) in the treatment of recurrent or locally advanced head and neck cancer. Results showed that the objective response rate (ORR) for all patients was 71%, and full response/PR was 50%/25% for R-SCC and 8%/62% for R/LA-nSCC. The 2-year OS rates were 58% (R-SCC) and 100% (R/LA-nSCC). The R-SCC median locoregional PFS (LRPFS) was 11.5 months.

Frequently observed adverse events included hair loss (95%), hyperthermia (86%), and nausea (81%), suggesting that BNCT using C-BENS with borofalan (¹⁰B) is a promising treatment option for head and neck R-SCC or R/LA-nSCC patients (37). Lan et al. performed BNCT on four SCC patients with BPA-F. The results showed that one carotid blowout syndrome (CBS)-related death occurred among patients with signs of CBS, and the others remained recovered until the last follow-up (median follow-up time was 15.1 months) (38).

Conclusions

Analyzing these clinical results, BNCT may be a good choice for the clinical diagnosis and treatment of cancer. In particular, BNCT has shown remarkable results for problems that are difficult to deal with conventional means. However, the patient situation is generally more complex and prone to various metastases. Secondly, the targeting ability of boron delivery agents also makes it difficult to make the distribution of boron greatly different between tumor and normal tissue. In the occurrence of nuclear reactions, it is inevitable to produce high-energy γ rays that are difficult to ignore, which will easily cause radioactive damage to the surrounding tissue. In addition, due to the relatively small number of patients currently receiving BNCT, long-term observation is still insufficient, and it is difficult to determine the prognostic impact, whether physical or psychological.

Funding

This work was supported by the Special Research Project of Lanzhou University Serving the Economic Social Development of Gansu Province (054000282) Lanzhou Talent Innovation and Entrepreneurship Project (2020-RC-38), the Fundamental Research Funds for the Central Universities (lzujbky-2020-kb14), and Major Science and Technology Special Project of Gansu Province (20ZD7FA003).

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  KagejiTNagahiroSMizobuchiYMatsuzakiKNakagawaYKumadaH. Boron Neutron Capture Therapy (BNCT) for Newly-Diagnosed Glioblastoma: Comparison of Clinical Results Obtained With BNCT and Conventional Treatment. J Med Invest (2014) 61:254–63. doi: 10.2152/jmi.61.254

  • CrossRef
  • Google Scholar

• 2

  MossRL. Critical Review, With an Optimistic Outlook, on Boron Neutron Capture Therapy 385 (BNCT). Appl Radiat Isot (2014) 88:2–11. doi: 10.1016/j.apradiso.2013.11.109

  • CrossRef
  • Google Scholar

• 3

  SuzukiM. Boron Neutron Capture Therapy (BNCT): A Unique Role in Radiotherapy With a View to Entering the Accelerator-Based BNCT Era. Int J Clin Oncol (2020) 25:43–50. doi: 10.1007/s10147-388019-01480-4

  • CrossRef
  • Google Scholar

• 4

  MaruyamaKIshidaOKasaokaSTakizawaTUtoguchiNShinoharaAet al. Intracellular Targeting of Sodium Mercaptoundecahydrododecaborate (BSH) to Solid Tumors by Transferrin-PEG Liposomes, for Boron Neutron-Capture Therapy (BNCT). J Control Release (2004) 98:195–207. doi: 10.1016/j.jconrel.2004.04.018

  • CrossRef
  • Google Scholar

• 5

  LanTLChouFILinKHPanPSLeeJCHuangWSet al. Using Salvage Boron Neutron Capture Therapy (BNCT) for Recurrent Malignant Brain Tumors in Taiwan. Appl Radiat Isotopes (2020) 160. doi: 10.1016/j.apradiso.2020.109105

  • CrossRef
  • Google Scholar

• 6

  HideghetyKSauerweinWHaselsbergerKGrochullaFFankhauserHMossRet al. Postoperative Treatment of Glioblastoma With BNCT at the Petten Irradiation Facility (EORTC Protocol 11961). Strahlenther Onkol (1999) 175:111–4. doi: 10.1007/Bf03038907

  • CrossRef
  • Google Scholar

• 7

  HideghétyKSauerweinWWittigAGotzCPaquisPGrochullaFet al. Tissue Uptake of BSH in Patients With Glioblastoma in the EORTC 11961 Phase I BNCT Trial. J Neuro-Oncol (2003) 62:145–56. doi: 10.1007/Bf02699941

  • CrossRef
  • Google Scholar

• 8

  JoensuuHKankaanrantaLSeppalaTAuterinenIKallioMKulvikMet al. Boron Neutron Capture Therapy of Brain Tumors: Clinical Trials at the Finnish Facility Using Boronophenylalanine. J Neuro-Oncol (2003) 62:123–34. doi: 10.1007/Bf02699939

  • CrossRef
  • Google Scholar

• 9

  GoodmanJHYangWBarthRFGaoZBoeselCPStaubusAEet al. Boron Neutron Capture Therapy of Brain Tumors: Biodistribution, Pharmacokinetics, and Radiation Dosimetry Sodium Borocaptate in Patients With Gliomas. Neurosurgery (2000) 47:608–21. doi: 10.1097/00006123-200009000-00016

  • CrossRef
  • Google Scholar

• 10

  BarthRFVicenteMGHHarlingOKKigerWSRileyKJBinnsPJet al. Current Status of Boron Neutron Capture Therapy of High Grade Gliomas and Recurrent Head and Neck Cancer. Radiat Oncol (2012) 7. doi: 10.1186/1748-717x-7-146

  • CrossRef
  • Google Scholar

• 11

  BarthRFZhangZLiuT. A Realistic Appraisal of Boron Neutron Capture Therapy as a Cancer Treatment Modality. Cancer Commun (Lond) (2018) 38:36. doi: 10.1186/s40880-018-0280-5

  • CrossRef
  • Google Scholar

• 12

  NakagawaYHatanakaH. Boron Neutron Capture Therapy. Clinical Brain Tumor Studies. J Neurooncol (1997) 33:105–15. doi: 10.1023/a:1005781517624

  • CrossRef
  • Google Scholar

• 13

  LocherG. Biological Effects and Therapeutic Possibilities of Neutrons. Am J Roentgenol Radium Ther (1936) 36:1–13.

  • Google Scholar

• 14

  FarrLESweetWHLocksleyHBRobertsonJS. Neutron Capture Therapy of Gliomas Using Boron. Trans Am Neurol Assoc (1954) 13:110–3.

  • Google Scholar

• 15

  BrownellGLMurrayBWSweetWHWellumGRSolowayAH. Proceedings: A Reassessmentas. Proc Natl Cancer Conf (1972) 7:827– 837.

  • Google Scholar

• 16

  HatanakaH. Clinical Results of Boron Neutron Capture Therapy. Basic Life Sci (1990) 54:15–21. doi: 10.1007/978-1-4684-5802-2_2

  • CrossRef
  • Google Scholar

• 17

  HatanakaHNakagawaY. Clinical-Results of Long-Surviving Brain-Tumor Patients Who Underwent Boron Neutron-Capture Therapy. Int J Radiat Oncol (1994) 28:1061–6. doi: 10.1016/0360-3016(94)90479-0

  • CrossRef
  • Google Scholar

• 18

  YongZSongZZhouYLiuTZhangZZhaoYet al. Boron Neutron Capture Therapy for Malignant Melanoma: First Clinical Case Report in China. Chin J Cancer Res (2016) 28:634–40. doi: 10.21147/j.issn.1000-9604.2016.06.10

  • CrossRef
  • Google Scholar

• 19

  SlatkinDN. A History of Boron Neutron-Capture Therapy of Brain-Tumors - Postulation of a Brain Radiation-Dose Tolerance Limit. Brain (1991) 114:1609–29. doi: 10.1093/brain/114.4.1609

  • CrossRef
  • Google Scholar

• 20

  BurianJJanskyBMarekMNovakEViererblLFernandesACet al. Development of Equipments for Determination of BNCT Source Spectral Parameters. Appl Radiat Isotopes (2004) 61:849–52. doi: 10.1016/j.apradiso.2004.05.064

  • CrossRef
  • Google Scholar

• 21

  BurianJMarekMRatajJFliborSRejchrtJVicrerblLet al. Report on the First Patient Group of the Phase I BNCT Trial at the LVR-15 Reactor. Int Congr Ser (2004) 1259:27–32. doi: 10.1016/S0531-5131(03)01515-2

  • CrossRef
  • Google Scholar

• 22

  CapalaJStenstamBHSkoldKSaf RosenscholdPMGiustiVPerssonCet al. Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden. J Neuro-Oncol (2003) 62:135–44. doi: 10.1023/A:1023230801571

  • CrossRef
  • Google Scholar

• 23

  SkoldKHSBDiazAZGiustiVPellettieriLHopewellJW. Boron Neutron Capture Therapy for Glioblastoma Multiforme: Advantage of Prolonged Infusion of BPA-F. Acta Neurol Scand (2010) 122:58–62. doi: 10.1111/j.1600-0404.2009.01267.x

  • CrossRef
  • Google Scholar

• 24

  MiyatakeSKajimotoYKawabataSYokoyamaKKuroiwaKOnoO. Modified Boron Neutron Capture Therapy (BNCT) for Malignant Gliomas Using Epithermal Neutron and Two Boron Compounds With Different Accumulation Mechanisms: Effectiveness of BNCT on Radiographic Images. Neuro-Oncology (2005) 7:349–50. doi: 10.3171/jns.2005.103.6.1000

  • CrossRef
  • Google Scholar

• 25

  MiyatakeSKawabataSKajimotoYAokiAHYokoyamaKYamadaMet al. Modified Boron Neutron Capture Therapy for Malignant Gliomas Performed Using Epithermal Neutron and Two Boron Compounds With Different Accumulation Mechanisms: An Efficacy Study Based on Findings on Neuroimages. J Neurosurg (2005) 103:1000–9. doi: 10.3171/jns.2005.103.6.1000

  • CrossRef
  • Google Scholar

• 26

  YamamotoTMatsumuraANakaiKShibataYEndoKSakuraiFet al. Current Clinical Results of the Tsukuba BNCT Trial. Appl Radiat Isot (2004) 61:1089–93. doi: 10.1016/j.apradiso.2004.05.010

  • CrossRef
  • Google Scholar

• 27

  KankaanrantaLSeppalaTKoivunoroHValimakiPBeuleACollanJet al. L-Boronophenylalanine-Mediated Boron Neutron Capture Therapy for Malignant Glioma Progressing After External Beam Radiation Therapy: A Phase I Study. Int J Radiat Oncol Biol Phys (2011) 80:369–76. doi: 10.1016/j.ijrobp.2010.02.031

  • CrossRef
  • Google Scholar

• 28

  MiyatakeSIKawabataSYokoyamaKKuroiwaTMichiueHSakuraiYet al. Survival Benefit of Boron Neutron Capture Therapy for Recurrent Malignant Gliomas. Appl Radiat Isotopes (2009) 67:S22–4. doi: 10.1016/j.apradiso.2009.03.032

  • CrossRef
  • Google Scholar

• 29

  MiyatakeSIKawabataSNonoguchiNYokoyamaKKuroiwaTMatsuiHet al. Pseudoprogression in Boron Neutron Capture Therapy for Malignant Gliomas and Meningiomas. Neuro-Oncology (2009) 11:430–6. doi: 10.1215/15228517-2008-107

  • CrossRef
  • Google Scholar

• 30

  WangLWLiuYHChouFIJiangSH. Clinical Trials for Treating Recurrent Head and Neck Cancer With Boron Neutron Capture Therapy Using the Tsing-Hua Open Pool Reactor. Cancer Commun (Lond) (2018) 38:37. doi: 10.1186/s40880-018-0295-y

  • CrossRef
  • Google Scholar

• 31

  GutinPHPiepmeierJMLunsfordLDLawsER. Boron Neutron Capture Therapy for Malignant Tumors Related to Meningiomas - Comments. Neurosurgery (2007) 61:90–1. doi: 10.1227/01.neu.0000279727.90650.24

  • CrossRef
  • Google Scholar

• 32

  WittigAColletteLAppelmanKBuhrmannSJackelMCJockelKHet al. EORTC Trial 11001: Distribution of Two 10B-Compounds in Patients With Squamous Cell Carcinoma of Head and Neck, a Translational Research/Phase 1 Trial. J Cell Mol Med (2009) 13:1653–65. doi: 10.1111/j.1582-4934.2009.00856.x

  • CrossRef
  • Google Scholar

• 33

  WittigAColletteLMossRSauerweinWA. Early Clinical Trial Concept for Boron Neutron Capture Therapy: A Critical Assessment of the EORTC Trial 11001. Appl Radiat Isotopes (2009) 67:S59–62. doi: 10.1016/j.apradiso.2009.03.012

  • CrossRef
  • Google Scholar

• 34

  KankaanrantaLSeppalaTKoivunoroHSaarilahtiKAtulaTCollanJet al. Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head-and-Neck Cancer: Final Analysis of a Phase I/II Trial. Int J Radiat Oncol Biol Phys (2012) 82:e67–75. doi: 10.1016/j.ijrobp.2010.09.057

  • CrossRef
  • Google Scholar

• 35

  WangLWWangSJChuPYHoCYJiangSHLiuYWet al. BNCT for Locally Recurrent Headand Neck Cancer: Preliminary Clinical Experience From a Phase I/II Trial at Tsing Hua Open-Pool Reactor. Appl Radiat Isot (2011) 69:1803–6. doi: 10.1016/j.apradiso.2011.03.008

  • CrossRef
  • Google Scholar

• 36

  WangLWChenYWHoCYHsueh LiuYWChouFILiuYHet al. Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial. Int J Radiat Oncol Biol Phys (2016) 95:396–403. doi: 10.1016/j.ijrobp.2016.02.028

  • CrossRef
  • Google Scholar

• 37

  HiroseKKonnoAHiratsukaJYoshimotoSKatoTOnoKet al. Boron Neutron Capture Therapy Using Cyclotron-Based Epithermal Neutron Source and Borofalan ((10)B) for Recurrent or Locally Advanced Head and Neck Cancer (JHN002): An Open-Label Phase II Trial. Radiother Oncol (2021) 155:182–7. doi: 10.1016/j.radonc.2020.11.001

  • CrossRef
  • Google Scholar

• 38

  LanTLChangFCWangCWIgawaKWuSHLoWLet al. Prevention and Early Management of Carotid Blowout Syndrome for Patients Receiving Head and Neck Salvage Boron Neutron Capture Therapy (BNCT). J Dent Sci (2021) 16:854–60. doi: 10.1016/j.jds.2020.12.013

  • CrossRef
  • Google Scholar

• 39

  MishimaYIchihashiMHattaSHondaCYamamuraKNakagawaTet al. First Human Linical Trial of Melanoma Neutron Capture. Diagn Ther Strahlenther Onkol (1989) 165:251–4.

  • Google Scholar

• 40

  MenendezPRRothBMCPereiraMDCasalMRGonzalezSJFeldDBet al. BNCT for Skin Melanoma in Extremities: Updated Argentine Clinical Results. Appl Radiat Isotopes (2009) 67:S50– S53. doi: 10.1016/j.apradiso.2009.03.020

  • CrossRef
  • Google Scholar

• 41

  WittigAMalagoMColletteLHuiskampRBuhrmannSNievaartVet al. Uptake of Two 10B-Compounds in Liver Metastases of Colorectal Adenocarcinoma for Extracorporeal Irradiation With Boron Neutron Capture Therapy (EORTC Trial 11001). Int J Cancer (2008) 122:1164–71. doi: 10.1002/ijc.23224

  • CrossRef
  • Google Scholar

• 42

  YanagieHHigashiSSeguchiKIkushimaIFujiharaMNonakaYet al. Pilot Clinical Study of Boron Neutron Capture Therapy for Recurrent Hepatic Cancer Involving the Intra-Arterial Injection of a (BSH)-B-10-Containing WOW Emulsion. Appl Radiat Isotopes (2014) 88:32–7. doi: 10.1016/j.apradiso.2014.01.014

  • CrossRef
  • Google Scholar

• 43

  HiratsukaJKamitaniNTanakaRYodenETokiyaRSuzukiMet al. Boron Neutron Capture Therapy for Vulvar Melanoma and Genital Extramammary Paget’s Disease With Curative Responses. Cancer Commun (Lond) (2018) 38:38. doi: 10.1186/s40880-018-0297-9

  • CrossRef
  • Google Scholar

• 44

  YinghuaiZYanKCJizhongLHweiCSHonYCEmiAet al. Iridium(I)-Salicylaldiminato-Cyclooctadiene Complexes Used as Catalysts for Phenylborylation. J Organomet Chem (2007) 692:4244–50. doi: 10.1016/j.jorganchem.2007.06.052

  • CrossRef
  • Google Scholar

• 45

  BarthRF. Boron Neutron Capture Therapy at the Crossroads: Challenges and Opportunities. Appl Radiat Isot (2009) 67:S3–6. doi: 10.1016/j.apradiso.2009.03.102

  • CrossRef
  • Google Scholar

• 46

  HawthorneMFLeeMW. A Critical Assessment of Boron Target Compounds for Boron Neutron Capture Therapy. J Neuro-Oncol (2003) 62:33–45. doi: 10.1023/A:1023253309343

  • CrossRef
  • Google Scholar

• 47

  LudererMJde la PuentePAzabAK. Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy. Pharm Res (2015) 32:2824–36. doi: 10.1007/s11095-015-1718-y

  • CrossRef
  • Google Scholar

• 48

  LesnikowskiZJParadowskaEOlejniczakABStudzinskaMSeekampPSchusslerUet al. Towards New Boron Carriers for Boron Neutron Capture Therapy: Metallacarboranes and Their Nucleoside Conjugates. Bioorg Med Chem (2005) 13:4168–75. doi: 10.1016/j.bmc.2005.04.042

  • CrossRef
  • Google Scholar

• 49

  YanagieHOgataASugiyamaHEriguchiMTakamotoSTakahashiH. Application of Drug Delivery System to Boron Neutron Capture Therapy for Cancer. Expert Opin Drug Del (2008) 5:427– 443. doi: 10.1517/17425247.5.4.427

  • CrossRef
  • Google Scholar

• 50

  ArchambeauJO. The Effect of Increasing Exposures of the 10-B(n,alpha)7-Li Reaction on the Skin of Man. Radiology (1970) 94:179–87. doi: 10.1148/10.1148/94.1.179

  • CrossRef
  • Google Scholar

• 51

  AsburyAKOjemannRGNielsenSLSweetWH. Neuropathologic Study of Fourteen Cases of Malignant Brain Tumor Treated by Boron-10 Slow Neutron Capture Radiation. J Neuropathol Exp Neurol (1972) 31:278–303. doi: 10.1097/00005072-197204000-00005

  • CrossRef
  • Google Scholar

• 52

  ChananaADCapalaJChadhaMCoderreJADiazAZElowitzEHet al. Boron Neutron Capture Therapy for Glioblastoma Multiforme: Interim Results From the Phase I/II Dose-Escalation Studies. Neurosurgery (1999) 44:1182–92; discussion 1192-1183. doi: 10.1097/00006123-199906000-00013

  • CrossRef
  • Google Scholar

• 53

  SolowayAHHatanakaHMAD. Penetration of Brain and Brain Tumor. VII. Tumor-Binding Sulfhydryl Boron Compounds. J Med Chem (1967) 10:714–7. doi: 10.1021/jm00316a042

  • CrossRef
  • Google Scholar

• 54

  HatanakaHSweetWHSanoKEllisF. The Present Status of Boron-Neutron Capture Therapy for Tumors. Pure Appl Chem (1991) 63:373–4. doi: 10.1351/pac199163030373

  • CrossRef
  • Google Scholar

• 55

  MishimaYHondaCIchihashiMObaraHHiratsukaJFukudaHet al. Treatment of Malignant Melanoma by Single Thermal Neutron Capture Therapy With Melanoma-Seeking 10B- Compound. Lancet (1989) 2:388–9. doi: 10.1016/s0140-6736(89)90567-9

  • CrossRef
  • Google Scholar

• 56

  FukudaHHiratsukaJKobayashiTSakuraiYYoshinoKKarashimaHet al. Boron Neutron Capture Therapy (BNCT) for Malignant Melanoma With Special Reference to Absorbed Doses to the Normal Skin and Tumor. Australas Phys Eng Sci Med (2003) 97. doi: 10.1007/BF03178777

  • CrossRef
  • Google Scholar

• 57

  BarthRFYangWLAl-MadhounASJohnsamuelJByunYChandraSet al. Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors. Cancer Res (2004) 64:6287–95. doi: 10.1158/0008-5472.Can-04-0437

  • CrossRef
  • Google Scholar

• 58

  BarthRFYangWLWuGSwindallMByunYJNarayanasamySet al. Thymidine Kinase 1 as a Molecular Target for Boron Neutron Capture Therapy of Brain Tumors. P Natl Acad Sci USA (2008) 105:17493–7. doi: 10.1073/pnas.0809569105

  • CrossRef
  • Google Scholar

• 59

  KhalilAIshitaKAliTTjarksW. N3-Substituted Thymidine Bioconjugates for Cancer Therapy and Imaging. Future Med Chem (2013) 5:677–92. doi: 10.4155/Fmc.13.31

  • CrossRef
  • Google Scholar

• 60

  SmilowitzHMSlatkinDNMiccaPLMiuraM. Microlocalization of Lipophilic Porphyrins: Non-Toxic Enhancers of Boron Neutron-Capture Therapy. Int J Radiat Biol (2013) 89:611–7. doi: 10.3109/09553002.2013.782446

  • CrossRef
  • Google Scholar

• 61

  HattoriYKusakaSMukumotoMIshimuraMOhtaYTakenakaHet al. Synthesis and In Vitro Evaluation of Thiododecaborated Alpha, Alpha- Cycloalkylamino Acids for the Treatment of Malignant Brain Tumors by Boron Neutron Capture Therapy. Amino Acids (2014) 46:2715–20. doi: 10.1007/s00726-014-1829-5

  • CrossRef
  • Google Scholar

• 62

  SoloshonokVASorochinskyAE. Practical Methods for the Synthesis of Symmetrically Alpha, Alpha-Disubstituted Alpha-Amino Acids. Synthesis-Stuttgart (2010) 2319–44. doi: 10.1055/s-0029-1220013

  • CrossRef
  • Google Scholar

• 63

  AhrensVMFrankRStadlbauerSBeck-SickingerAGHey-HawkinsE. Incorporation of Ortho-Carbaboranyl-Nepsilon-Modified L-Lysine Into Neuropeptide Y Receptor Y1- and Y2-Selective Analogues. J Med Chem (2011) 54:2368–77. doi: 10.1021/jm101514m

  • CrossRef
  • Google Scholar

• 64

  SnyderHRReedyAJLennarzWJ. Synthesis of Aromatic Boronic Acids. Aldehydo Boronic Acids and a Boronic Acid Analog of Tyrosine. J Am Chem Soc (1958) 80:835–8. doi: 10.1021/ja01537a021

  • CrossRef
  • Google Scholar

• 65

  DiazAZ. Assessment of the Results From the Phase FII Boron Neutron Capture Therapy Trials at the Brookhaven National Laboratory From a Clinician’s Point of View. J Neuro-Oncol (2003) 62:101–9. doi: 10.1007/BF02699937

  • CrossRef
  • Google Scholar

• 66

  HattoriYKusakaSMukumotoMUeharaKAsanoTSuzukiMet al. Biological Evaluation of Dodecaborate-Containing L-Amino Acids for Boron Neutron Capture Therapy. J Med Chem (2012) 55:6980–4. doi: 10.1021/jm300749q

  • CrossRef
  • Google Scholar

• 67

  Al-MadhounASJohnsamuelJBarthRFTjarksWErikssonS. Evaluation of Human Thymidine Kinase 1 Substrates as New Candidates for Boron Neutron Capture Therapy. Cancer Res (2004) 64:6280–6. doi: 10.1158/0008-5472.Can-04-0197

  • CrossRef
  • Google Scholar

• 68

  ByunYThirumamagalBTSYangWLErikssonSBarthRFTjarksW. Preparation and Biological Evaluation of B-10-Enriched 3-[5-{2-(2,3-Dihydroxyprop-1-Yl)-O-Carboran-1-Yl}Pentan-1-Yl]Thymidine (N5-2OH), a New Boron Delivery Agent for Boron Neutron Capture Therapy of Brain Tumors. J Med Chem (2006) 49:5513–23. doi: 10.1021/jm060413w

  • CrossRef
  • Google Scholar

• 69

  MiuraMMiccaPLHeinrichsJCGabelDFairchildRGSlatkinDN. Biodistribution and Toxicity of 2,4-Divinyl-Nido-O-Carboranyldeuteroporphyrin IX in Mice. Biochem Pharmacol (1992) 43:467–76. doi: 10.1016/0006-2952(92)90565-z

  • CrossRef
  • Google Scholar

• 70

  MiuraMMiccaPLFisherCDHeinrichsJCDonaldsonJAFinkelGCet al. Synthesis of a Nickel Tetracarboranylphenylporphyrin for Boron Neutron-Capture Therapy: Biodistribution and Toxicity in Tumor-Bearing Mice. Int J Cancer (1996) 68:114–9. doi: 10.1002/(SICI)1097-0215(19960927)68:1<114::AID-IJC20>3.0.CO;2-A

  • CrossRef
  • Google Scholar

• 71

  MiuraMMiccaPLFisherCDGordonCRHeinrichsJCSlatkinDN. Evaluation of Carborane-Containing Porphyrins as Tumour Targeting Agents for Boron Neutron Capture Therapy. Brit J Radiol (1998) 71:773–81. doi: 10.1259/bjr.71.847.9771389

  • CrossRef
  • Google Scholar

• 72

  MiuraMMorrisGMMiccaPLLombardoDTYoungsKMKalef-EzraJAet al. Boron Neutron Capture Therapy of a Murine Mammary Carcinoma Using a Lipophilic Carboranyltetraphenylporphyrin. Radiat Res (2001) 155:603–10. doi: 10.1667/0033-7587(2001)155[0603:Bnctoa]2.0.Co;2

  • CrossRef
  • Google Scholar

• 73

  MiuraMMorrisGMMiccaPLNawrockyMMMakarMSCookSPet al. Synthesis of Copper 601 Octabromotetracarboranylphenylporphyrin for Boron Neutron Capture Therapy and Its Toxicity and Biodistribution in Tumour-Bearing Mice. Brit J Radiol (2004) 77:573–80. doi: 10.1259/bjr/71404908

  • CrossRef
  • Google Scholar

• 74

  MiuraMMorrisGMHopewellJWMiccaPLMakarMSNawrockyMMet al. Enhancement 604 of the Radiation Response of EMT-6 Tumours by a Copper Octabromotetracarboranylphenylporphyrin. Brit J Radiol (2012) 85:443–50. doi: 10.1259/bjr/87260973

  • CrossRef
  • Google Scholar

• 75

  InoueMTeradaTOkudaMInuiK. Regulation of Human Peptide Transporter 1 (PEPT1) in Gastric Cancer Cells by Anticancer Drugs. Cancer Lett (2005) 230:72–80. doi: 10.1016/j.canlet.2004.12.023

  • CrossRef
  • Google Scholar

• 76

  WormDJHoppenzPEls-HeindlSKellertMKuhnertRSaretzSet al. Selective Neuropeptide Y Conjugates With Maximized Carborane Loading as Promising Boron Delivery Agents for Boron Neutron Capture Therapy. J Med Chem (2020) 63:2358–71. doi: 10.1021/acs.jmedchem.9b01136

  • CrossRef
  • Google Scholar

• 77

  MiyabeJOhgakiRSaitoKWeiLQuanLJinCet al. Boron Delivery for Boron Neutron Capture Therapy Targeting a Cancer-Upregulated Oligopeptide Transporter. J Pharmacol Sci (2019) 139:215–22. doi: 10.1016/j.jphs.2019.01.012

  • CrossRef
  • Google Scholar

• 78

  SollRMDingerMCLundellILarhammerDBeck-SickingerAG. Novel Analogues of 617 Neuropeptide Y With a Preference for the Y1-Receptor. Eur J Biochem (2001) 268:2828–37. doi: 10.1046/j.1432-1327.2001.02161.x

  • CrossRef
  • Google Scholar

• 79

  WongSF. Cetuximab: An Epidermal Growth Factor Receptor Monoclonal Antibody for the Treatment of Colorectal Cancer. Clin Ther (2005) 27:684–94. doi: 10.1016/j.clinthera.2005.06.003

  • CrossRef
  • Google Scholar

• 80

  WuGBarthRFYangWLChatterjeeMTjarksWCiesielskiMJet al. Site-Specific Conjugation of Boron-Containing Dendrimers to Anti-EGF Receptor Monoclonal Antibody Cetuximab (IMC-C225) and Its Evaluation as a Potential Delivery Agent for Neutron Capture Therapy. Bioconjug Chem (2004) 15:185–94. doi: 10.1021/bc0341674

  • CrossRef
  • Google Scholar

• 81

  WuGYangWLBarthRFKawabataSSwindallMBandyopadhyayaAKet al. Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor-Positive Glioma Using Boronated Cetuximab. Clin Cancer Res (2007) 13:1260–8. doi: 10.1158/1078-0432.Ccr-06-2399

  • CrossRef
  • Google Scholar

• 82

  PanXGWuGYangWLBarthRFTjarksWLeeRJ. Synthesis of Cetuximab-Immunoliposomes via a Cholesterol-Based Membrane Anchor for Targeting of EGFR. Bioconjug Chem (2007) 18:101–8. doi: 10.1021/bc060174r

  • CrossRef
  • Google Scholar

• 83

  YangWLBarthRFWuGKawabataSSferraTJBandyopadhyayaAKet al. Molecular Targeting and Treatment of EGFRvIII-Positive Gliomas Using Boronated Monoclonal Antibody L8A4. Clin Cancer Res (2006) 12:3792–802. doi: 10.1158/1078-0432.Ccr-06-0141

  • CrossRef
  • Google Scholar

• 84

  KouriMKankaanrantaLSeppalaTTervoLRasilainenMMinnHet al. Undifferentiated Sinonasal Carcinoma May Respond to Single-Fraction Boron Neutron Capture Therapy. Radiother Oncol (2004) 72:83–5. doi: 10.1016/j.radonc.2004.03.016

  • CrossRef
  • Google Scholar

• 85

  VerbakelWFSauerweinWHideghetyKStecher-RasmussenF. Boron Concentrations in Brain During Boron Neutron Capture Therapy: In Vivo Measurements From the Phase I Trial EORTC 11961 Using a Gamma-Ray Telescope. Int J Radiat Oncol Biol Phys (2003) 55:743–56. doi: 10.1016/s0360-3016(02)04392-4

  • CrossRef
  • Google Scholar

• 86

  VosMJTurowskiBZanellaFEPaquisPSiefertAHideghetyKet al. Radiologic Findings in Patients Treated With Boron Neutron Capture Therapy for Glioblastoma Multiforme Within EORTC Trial 11961. Int J Radiat Oncol Biol Phys (2005) 61:392–9. doi: 10.1016/j.ijrobp.2004.06.008

  • CrossRef
  • Google Scholar

• 87

  KawabataSMiyatakeSHiramatsuRHirotaYMiyataSTakekitaYet al. Phase II Clinical Study of Boron Neutron Capture Therapy Combined With X-Ray Radiotherapy/Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme–Study Design and Current Status Report. Appl Radiat Isot (2011) 69:1796–9. doi: 10.1016/j.apradiso.2011.03.014

  • CrossRef
  • Google Scholar

• 88

  KagejiTMizobuchiYNagahiroSNakagawaYKumadaH. Clinical Results of Boron Neutron Capture Therapy (BNCT) for Glioblastoma. Appl Radiat Isot (2011) 69:1823–5. doi: 10.1016/j.apradiso.2011.05.029

  • CrossRef
  • Google Scholar

• 89

  StaianoJJWongLButlerJSearleAEBartonDPJHarrisPA. Flap Reconstruction Following Gynaecological Tumour Resection for Advanced and Recurrent Disease - A 12 Year Experience. J Plast Reconstr Aes (2009) 62:346–51. doi: 10.1016/j.bjps.2007.12.050

  • CrossRef
  • Google Scholar

• 90

  WolchokJDChiarion-SileniVGonzalezRRutkowskiPGrobJJCoweyCLet al. Overall Survival With Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med (2017) 377:1345–56. doi: 10.1056/NEJMoa1709684

  • CrossRef
  • Google Scholar

• 91

  LarkinJChiarion-SileniVGonzalezRGrobJCoweyCLaoCet al. Overall Survival With Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med (2019) 379:2185–5. doi: 10.1056/NEJMoa1910836

  • CrossRef
  • Google Scholar

• 92

  GonzalezSJBonomiMRCruzGASBlaumannHRLarrieuOACMenendezPet al. First BNCT Treatment of a Skin Melanoma in Argentina: Dosimetric Analysis and Clinical Outcome. Appl Radiat Isotopes (2004) 61:1101–5. doi: 10.1016/j.apradiso.2004.05.060

  • CrossRef
  • Google Scholar

• 93

  KeGSunZShenFLiuTLiYZhouY. The Study of Physics and Thermal Characteristics for in-Hospital Neutron Irradiator (IHNI). Appl Radiat Isot (2009) 67:S234–237. doi: 10.1016/j.apradiso.2009.03.117

  • CrossRef
  • Google Scholar

• 94

  FukudaHHiratsukaJHondaCKobayashiTYoshinoKKarashimaHet al. Boron Neutron Capture Therapy of Malignant Melanoma Using 10B-Paraboronophenylalanine With Special Reference to Evaluation of Radiation Dose and Damage to the Normal Skin. Radiat Res (1994) 138:435–42. doi: 10.2307/3578693

  • CrossRef
  • Google Scholar

• 95

  BlaumannHRGonzalezSJLonghinoJCruzGASLarrieuOACBonomiMRet al. Boron Neutron Capture Therapy of Skin Melanomas at the RA-6 Reactor: A Procedural Approach to Beam Set Up and Performance Evaluation for Upcoming Clinical Trials. Med Phys (2004) 31:70–80. doi: 10.1118/1.1631915

  • CrossRef
  • Google Scholar

• 96

  HiratsukaJKamitaniNTanakaRTokiyaRYodenESakuraiYet al. Long-Term Outcome of Cutaneous Melanoma Patients Treated With Boron Neutron Capture Therapy (BNCT). J Radiat Res (2020) 61:945–51. doi: 10.1093/jrr/rraa068

  • CrossRef
  • Google Scholar

• 97

  Kaidar-PersonOGilZBillanS. Precision Medicine in Head and Neck Cancer. Drug Resist Update (2018) 40:13–6. doi: 10.1016/j.drup.2018.09.001

  • CrossRef
  • Google Scholar

• 98

  LeeTWLaiAHarmsJKSingletonDCDicksonBDMacannAMJet al. Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment 686 in Head and Neck Cancer. Cancers (Basel) (2020) 12. doi: 10.3390/cancers12123743

  • CrossRef
  • Google Scholar

• 99

  KankaanrantaLSeppalaTKoivunoroHSaarilahtiKAtulaTCollanJet al. Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head and Neck Cancer. Int J Radiat Oncol (2007) 69:475–82. doi: 10.1016/j.ijrobp.2007.03.039

  • CrossRef
  • Google Scholar

• 100

  WongSJMachtayMLiY. Locally Recurrent, Previously Irradiated Head and Neck Cancer: Concurrent Re-Irradiation and Chemotherapy, or Chemotherapy Alone? J Clin Oncol (2006) 24:2653–8. doi: 10.1200/Jco.2005.05.3850

  • CrossRef
  • Google Scholar