AB015. Efficacy and safety of boron neutron capture therapy in managing metastatic spinal tumors: experimental findings.

BACKGROUND: Boron neutron capture therapy (BNCT) is a unique cancer treatment modality that enables precise targeting of tumors at the cellular level. Based on the success observed in nuclear reactors, BNCT now holds promise as a therapeutic approach for treating invasive brain tumors or head and neck cancers. Metastatic spinal tumors have been treated with multidisciplinary interventions such as surgical resection and radiation therapy. Despite recent advantages of radiation therapy, it remains challenging to achieve better quality of life and activity of daily living. The purpose of this study was to evaluate the efficacy and safety of BNCT in metastatic spinal tumor using a mouse model. METHODS: For the in vitro, neutron and photon irradiation was applied to A549 human lung adenocarcinoma cells. The cells were irradiated neutrons with or without p-boronophenylalanine (BPA) 10 µg Boron/mL for a 24-h exposure before neutron irradiation. The difference of biological effect between neutrons and photons was evaluated by colony forming assay. For in vivo, the tumor-bearing mice were intravenously administered BPA (250 mg/kg), followed by measuring biodistribution of boron using inductively coupled plasma atomic emission spectroscopy (ICP-AES). For in vivo BNCT, the mice were randomly assigned to untreated (n=10), neutron irradiation only (n=9), and BNCT groups (n=10). Overall survival and hindlimb function were analyzed. Histopathological examination was also performed to assess the influences of neutron irradiation. RESULTS: Neutron irradiation showed a stronger cell-killing effect than that exhibited by photon irradiation in vitro. For in vivo biodistribution, the highest boron accumulation in the tumor was seen at 2.5-h time point (10.5 µg B/g), with a tumor to normal spinal cord and blood ratios were 3.6 and 2.9, respectively. For the in vivo BNCT, BNCT had significantly prolonged survival (vs. untreated, P=0.002; vs. neutron only, P=0.01, respectively, log-rank test) and preserved mice hindlimb function compared to the other groups (vs. untreated, P<0.001; vs. neutron only, P=0.005, respectively, MANOVA). No adverse events and apparent histopathological changes were observed among three groups. CONCLUSIONS: These findings indicate that BNCT may represent a novel therapeutic option in the management of metastatic spinal tumors.

[Chasing New Cancer Treatments: Current Status and Future Development of Boron Neutron Capture Therapy].

Boron neutron capture therapy (BNCT) is expected to be a promising next-generation cancer treatment. In 2020, Japan, which has led the research on this treatment modality, was the first country in the world to approve BNCT. The boron agents that have been clinically applied in BNCT include a caged boron compound (mercaptoundecahydrododecaborate: BSH) and a boron-containing amino acid (p-boronophenylalanine: BPA). In particular, the BPA preparation Steboronine® is the only approved drug for BNCT. However, the problem with BPA is that it is poorly retained in the tumor and has very low solubility in water. This cannot be overlooked for BNCT, which requires large amounts of boron in the tumor. The high dosage volume, together with low tumor retention, leads to reduced therapeutic efficacy and increased physical burden on the patient. In the case of BSH, its insufficient penetration into the tumor is problematic. Based on drug delivery system (DDS) technology, we have developed a next-generation boron pharmaceutical superior to Steboronine®. Our approach involves the redevelopment of BPA using innovative ionic liquid formulation technology. Here, we describe previous boron agents and introduce our recent efforts in the development of boron compounds.

In silico assessments of the small molecular boron agents to pave the way for artificial intelligence-based boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a highly targeted, selective and effective technique to cure various types of cancers, with less harm to the healthy cells. In principle, BNCT treatment needs to distribute the 10boron (10B) atoms inside the tumor tissues, selectively and homogeneously, as well as to initiate a nuclear fission reaction by capturing sufficient neutrons which releases high linear energy particles to kill the tumor cells. In BNCT, it is crucial to have high quality boron agents with acceptable bio-selectivity, homogeneous distribution and deliver in required quantity, similar to chemotherapy and other radiotherapy for tumor treatment. Nevertheless, boron drugs currently used in clinical trials yet to meet the full requirements. On the other hand, BNCT processing has opened up the era of renaissance due to the advanced development of the high-quality neutron source and the global construction of new BNCT centers. Consequently, there is an urgent need to use boron agents that have increased biocapacity. Artificial intelligence (AI) tools such as molecular docking and molecular dynamic simulation technologies have been utilized to develop new medicines. In this work, the in silico assessments including bioinformatics assessments of BNCT related tumoral receptor proteins, computational assessments of optimized small molecules of boron agents, are employed to speed up the screening process for boron drugs. The outcomes will be applicable to pave the way for future BNCT that utilizes artificial intelligence. The in silico molecular docking and dynamic simulation results of the optimized small boron agents, such as 4-borono-l-phenylalanine (BPA) with optimized proteins like the L-type amino acid transporter 1 (LTA1, also known as SLC7A5) will be examined. The in silico assessments results will certainly be helpful to researchers in optimizing druggable boron agents for the BNCT application. The clinical status of the optimized proteins, which are highly relevant to cancers that may be treated with BNCT, has been assessed using bioinformatics technology and discussed accordingly. Furthermore, the evaluations of cytotoxicity (IC50), boron uptake and tissue distribution of the optimized ligands 1 and 7 have been presented.

A national survey of medical staffs' required capability and workload for accelerator-based boron neutron capture therapy.

This study aimed to identify the required capabilities and workload of medical staff in accelerator-based boron neutron capture therapy (BNCT). From August to September 2022, a questionnaire related to the capabilities and workload in the accelerator-based BNCT was administered to 12 physicians, 7 medical physicists and 7 radiological technologists engaged in BNCT and 6 other medical physicists who were not engaged in BNCT to compare the results acquired by those engaged in BNCT. Only 6-21% of patients referred for BNCT received it. Furthermore, 30-75% of patients who received BNCT were treated at facilities located within their local district. The median required workload per treatment was 55 h. Considering additional workloads for ineligible patients, the required workload reached ~1.2 times longer than those for only eligible patients' treatment. With respect to capabilities, discrepancies were observed in treatment planning, quality assurance and quality control, and commissioning between medical physicists and radiological technologists. Furthermore, the specialized skills required by medical physicists are impossible to acquire from the experience of conventional radiotherapies as physicians engaged in BNCT were specialized not only in radiation oncology, but also in other fields. This study indicated the required workload and staff capabilities for conducting accelerator-based BNCT considering actual clinical conditions. The workload required for BNCT depends on the occupation. It is necessary to establish an educational program and certification system for the skills required to safely and effectively provide BNCT to patients.

Evaluation of sodium borocaptate (BSH) and boronophenylalanine (BPA) as boron delivery agents for neutron capture therapy (NCT) of cancer: an update and a guide for the future clinical evaluation of new boron delivery agents for NCT.

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. First, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. Second, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. Third, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.

Prognostic assessment of 18F-boronophenylalanine positron emission tomography (BPA-PET) in salvage boron neutron capture therapy for malignant brain tumors.

Background: Boron neutron capture therapy (BNCT) stands out as a propitious anti-cancer modality. 18F-boronophenylalanine positron emission tomography (BPA-PET) holds the potential to ascertain the concentration of BPA within the tumor, enabling meticulous treatment planning and outcome evaluation. However, no studies have been conducted on comparing the outcomes of those treated with BNCT to those who did not undergo this therapy. This study endeavors to analyze the correlation between BPA-PET and BNCT in the context of malignant brain tumors, and assess the survival outcomes following BNCT. Methods: A cohort study was performed on patients who underwent BPA-PET between February 2017 and April 2022 in our hospital. Patients were stratified into two groups: those subjected to BNCT (Group 1) and those not (Group 2). The tumor to normal tissue (T/N) ratio derived from BPA-PET was set at 2.5. The findings were scrutinized based on clinical follow-up. Student's t-test and Chi-squared test were employed to discern differences between the groups. A cumulative survival curve was constructed employing the Kaplan-Meier method. Differences were considered statistically significant at P<0.05. Results: In total, 116 patients with T/N ratios obtained from BPA-PET were enrolled. BNCT was administered to 58 patients, while mortality was observed in 100 patients. The median overall survival (OS) for the two groups was 8.5 and 6.0 months, respectively. The cumulative OS exhibited no significant discrepancy between the two groups, nor in their T/N ratios. Within Group 1, 44 out of 58 (75.9%) patients exhibited T/N ratios exceeding 2.5. Excluding 3 patients who expired within 3 months, 55 out of 58 patients were evaluated for response after BNCT. The objective response rate (ORR) was 30.9%. Patients achieving ORR displayed substantially higher survival rates compared to those without (median OS 13.5 vs. 8.3 months, P=0.0021), particularly when T/N ratio exceeded 2.5 (median OS 14.8 vs. 9.0 months, P=0.0199). Conclusions: BNCT does not appear indispensable for prolonging the survival of patients afflicted with malignant brain tumors. Nevertheless, it proves advantageous when ORR is attained, a condition closely linked to the values of T/N ratio derived from BPA-PET.

BNCT pancreatic cancer treatment strategy with glucose-conjugated boron drug.

Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer.

The Effects of Boron Neutron Capture Therapy on the Lungs in Recurrent Breast Cancer Treatment.

Boron neutron capture therapy (BNCT) has predominantly been performed for brain tumors or head and neck cancers. Although BNCT is known to be applicable to breast cancer, it has only been performed in a few cases involving thoracic region irradiation with reactor-based BNCT systems. Thus, there are very few reports on the effects of BNCT on the thoracic region and no reports of BNCT for breast cancer with accelerator-based BNCT systems. This paper introduces the world's first clinical study employing an accelerator-based BNCT system targeting recurrent breast cancer after radiation therapy. We aim to assess the efficacy and safety of BNCT, focusing on the dose response in the thoracic region, especially concerning the potential for radiation pneumonitis. Preliminary findings from the first three cases indicate no evidence of radiation pneumonitis within three months post treatment. This study not only establishes a foundation for novel breast cancer treatment options but also contributes significantly to the field of BNCT in the thoracic region.

A method for delivering the required neutron fluence in an accelerator-based boron neutron capture therapy system employing a lithium target.

Accelerator-based boron neutron capture therapy (BNCT) systems employing a solid-state lithium target indicated the reduction of neutron flux over the lifetime of a target, and its reduction could represent the neutron flux model. This study proposes a novel compensatory approach for delivering the required neutron fluence and validates its clinical applicability. The proposed approach relies on the neutron flux model and the cumulative sum of real-time measurements of proton charges. The accuracy of delivering the required neutron fluence for BNCT using the proposed approach was examined in five Li targets. With the proposed approach, the required neutron fluence could be delivered within 3.0%, and within 1.0% in most cases. However, those without using the proposed approach exceeded 3.0% in some cases. The proposed approach can consider the neutron flux reduction adequately and decrease the effect of uncertainty in neutron measurements. Therefore, the proposed approach can improve the accuracy of delivering the required fluence for BNCT even if a neutron flux reduction is expected during treatment and over the lifetime of the Li target. Additionally, by adequately revising the approach, it may apply to other type of BNCT systems employing a Li target, furthering research in this direction.

Accurate gamma-ray dose measurement up to 10 MeV by glass dosimeter with a sensitivity control filter for BNCT.

Glass dosimeters are very useful and convenient detection elements in radiation dosimetry. In this study, this glass dosimeter was applied to a BNCT treatment field. Boron Neutron Capture Therapy (BNCT) is a next-generation radiation therapy that can selectively kill only cancer cells. In the BNCT treatment field, both neutrons and secondary gamma-rays are generated. In other words, it is a mixed radiation field of neutrons and gamma-rays. We thus proposed a novel method to measure only gamma-ray dose in the mixed field using two RPLGD (Radiophoto-luminescence Glass Dosimeter) and two sensitivity control filters in order to control the dose response of the filtered RPLGD to be proportional to the air kerma coefficients, even if the gamma-ray energy spectrum is unknown. As the filter material iron was selected, and it was finally confirmed that reproduction of the air kerma coefficients was excellent within an error of 5.3% in the entire energy range up to 10 MeV. In order to validate this method, irradiation experiments were carried out using standard gamma-ray sources. As the result, the measured doses were in acceptably good agreement with the theoretical calculation results by PHITS. In the irradiation experiment with a volume source in a nuclear fuel storage room, the measured dose rates showed larger compared with survey meter values. In conclusion, the results of the standard sources showed the feasibility of this method, however for the volume source the dependence of the gamma-ray incident angle on the dosimeter was found to be not neglected. In the next step, it will be necessary to design a thinner filter in order to suppress the effect of the incident angle.

Carborane-FAPI conjugate: A potential FAP-targeted boron agent with improved boron content.

Boron neutron capture therapy (BNCT) has received extensive attention as an advanced binary radiotherapy method. However, BNCT still faces poor selectivity of boron agent and is insufficient boron content in tumor tissues. To improve the tumor-targeted ability and boron content, this research aims to design, synthesize and preliminary evaluate a new borane agent Carborane-FAPI, which coupling the o-carborane to the compound skeleton of a mature fibroblast activating protein (FAP) inhibitor (FAPI). FAP is a tumor-associated antigen. FAP expressed lowly in normal organs and highly expressed in tumors, so it is a potential target for diagnosis and treatment. Boronophenylalanine (BPA) is the most widely investigated BNCT drug in present. Compared with BPA, the boron content of a single molecule is increased and drug targeting is enhanced. The results show that Carboaren-FAPI has low toxicity to normal cells, and selective enrichment in tumor tissues. It is a promising boron drug that has the potential to be used in BNCT.

Translational research of boron neutron capture therapy for spinal cord gliomas using rat model.

Boron neutron capture therapy (BNCT) is a type of targeted particle radiation therapy with potential applications at the cellular level. Spinal cord gliomas (SCGs) present a substantial challenge owing to their poor prognosis and the lack of effective postoperative treatments. This study evaluated the efficacy of BNCT in a rat SCGs model employing the Basso, Beattie, and Bresnahan (BBB) scale to assess postoperative locomotor activity. We confirmed the presence of adequate in vitro boron concentrations in F98 rat glioma and 9L rat gliosarcoma cells exposed to boronophenylalanine (BPA) and in vivo tumor boron concentration 2.5 h after intravenous BPA administration. In vivo neutron irradiation significantly enhanced survival in the BNCT group when compared with that in the untreated group, with a minimal BBB scale reduction in all sham-operated groups. These findings highlight the potential of BNCT as a promising treatment option for SCGs.

The current status and novel advances of boron neutron capture therapy clinical trials.

Boron neutron capture therapy (BNCT) is a treatment method that focuses on improving the cure rate of patients with cancer who are difficult to treat using traditional clinical methods. By utilizing the high neutron absorption cross-section of boron, material rich in boron inside tumor cells can absorb neutrons and release high-energy ions, thereby destroying tumor cells. Owing to the short range of alpha particles, this method can precisely target tumor cells while minimizing the inflicted damage to the surrounding normal tissues, making it a potentially advantageous method for treating tumors. Globally, institutions have progressed in registered clinical trials of BNCT for multiple body parts. This review summarized the current achievements in registered clinical trials, Investigator-initiated clinical trials, aimed to integrate the latest clinical research literature on BNCT and to shed light on future study directions.

Safety of Boron Neutron Capture Therapy with Borofalan(10B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance.

BACKGROUND: This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). METHODS: This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. RESULTS: The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. CONCLUSIONS: This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting.

A study on the treatment of brain tumors with BNCT using several moderators with different thicknesses.

Boron neutron capture therapy (BNCT) is an effective binary radiation therapy that depends on nuclear capture reactions. In recent years, BNCT can be performed without a reactor owing to the development of accelerator-based neutron sources. A new BNCT irradiation facility is proposed, which is based on a 15 mA 2.5 MeV proton accelerator with a 100 µm thickness natural lithium target as a neutron converter. A great quantity of studies has shown that neutron beams with different spectra have unique therapeutic effects on tumors. An appropriate neutron beam for BNCT is obtained by Beam Shaping Assembly (BSA) and the moderator plays a main role in determining the BSA outlet beam spectrum. To figure out the dose distribution in phantom with various kinds of neutron spectrum modes during BNCT, a series of cases are calculated by MCNPX code. The results give a database for treatment of brain tumors with BNCT by using different moderators.

Feasibility study of optical imaging of the boron-dose distribution by a liquid scintillator in a clinical boron neutron capture therapy field.

BACKGROUND: Evaluation of the boron dose is essential for boron neutron capture therapy (BNCT). Nevertheless, a direct evaluation method for the boron-dose distribution has not yet been established in the clinical BNCT field. To date, even in quality assurance (QA) measurements, the boron dose has been indirectly evaluated from the thermal neutron flux measured using the activation method with gold foil or wire and an assumed boron concentration in the QA procedure. Recently, we successfully conducted optical imaging of the boron-dose distribution using a cooled charge-coupled device (CCD) camera and a boron-added liquid scintillator at the E-3 port facility of the Kyoto University Research Reactor (KUR), which supplies an almost pure thermal neutron beam with very low gamma-ray contamination. However, in a clinical accelerator-based BNCT facility, there is a concern that the boron-dose distribution may not be accurately extracted because the unwanted luminescence intensity, which is irrelevant to the boron dose is expected to increase owing to the contamination of fast neutrons and gamma rays. PURPOSE: The purpose of this research was to study the validity of a newly proposed method using a boron-added liquid scintillator and a cooled CCD camera to directly observe the boron-dose distribution in a clinical accelerator-based BNCT field. METHOD: A liquid scintillator phantom with 10 B was prepared by filling a small quartz glass container with a commercial liquid scintillator and boron-containing material (trimethyl borate); its natural boron concentration was 1 wt%. Luminescence images of the boron-neutron capture reaction were obtained in a water tank at several different depths using a CCD camera. The contribution of background luminescence, mainly due to gamma rays, was removed by subtracting the luminescence images obtained using another sole liquid scintillator phantom (natural boron concentration of 0 wt%) at each corresponding depth, and a depth profile of the boron dose with several discrete points was obtained. The obtained depth profile was compared with that of calculated boron dose, and those of thermal neutron flux which were experimentally measured or calculated using a Monte Carlo code. RESULTS: The depth profile evaluated from the subtracted images indicated reasonable agreement with the calculated boron-dose profile and thermal neutron flux profiles, except for the shallow region. This discrepancy is thought to be due to the contribution of light reflected from the tank wall. The simulation results also demonstrated that the thermal neutron flux would be severely perturbed by the 10 B-containing phantom if a relatively larger container was used to evaluate a wide range of boron-dose distributions in a single shot. This indicates a trade-off between the luminescence intensity of the 10 B-added phantom and its perturbation effect on the thermal neutron flux. CONCLUSIONS: Although a partial discrepancy was observed, the validity of the newly proposed boron-dose evaluation method using liquid-scintillator phantoms with and without 10 B was experimentally confirmed in the neutron field of an accelerator-based clinical BNCT facility. However, this study has some limitations, including the trade-off problem stated above. Therefore, further studies are required to address these limitations.

Fluorinated borono-phenylalanine for optimizing BNCT: Enhancing boron absorption against hydrogen scattering for thermal neutrons.

BACKGROUND: Boron-containing compounds, such as 4-borono-phenylalanine (BPA) are used as drugs for cancer treatment in the framework of Boron Neutron Capture Therapy (BNCT). Neutron irradiation of boron-rich compounds delivered to cancer cells triggers nuclear reactions that destroy cancer cells. PURPOSE: We provide a modeling of the thermal neutron cross section of BPA, a drug used in Boron Neutron Capture Therapy (BNCT), to quantify the competing contributions of boron absorption against hydrogen scattering, for optimizing BNCT by minimizing the latter. METHODS: We perform the experimental determination of the total neutron scattering cross section of BPA at thermal and epithermal neutron energies using neutron transmission measurements. We isolate the contribution related to the incoherent scattering by hydrogen atoms as a function of the neutron energy by means of the Average Functional Group Approximation, and we calculate the probability for a neutron of being absorbed as a function of the neutron energy both for BPA and for its variants where either one or all four aromatic hydrogen atoms are substituted by 19 F, and both for the samples with natural occurrence or enriched concentration of 10 B. RESULTS: While referring to the already available literature for in vivo use of fluorinated BPA, we show that fluorine-rich variants of BPA increase the probability of neutrons being captured by the molecule. As the higher absorption efficiency of fluorinated BPA does not depend on whether the molecule is used in vivo or not, our results are promising for the higher efficiency of the boron neutron capture treatment. CONCLUSIONS: Our results suggest a new advantage using fluorinated compounds for BNCT, in their optimized interaction with neutrons, in addition to their already known capability to be used for monitoring and pharmacokinetics studies using 19 F-Nuclear Magnetic Resonance or in 18 F-Positron Emission Tomography.

Targeted strategies to deliver boron agents across the blood-brain barrier for neutron capture therapy of brain tumors.

Boron neutron capture therapy (BNCT), as an innovative radiotherapy technology, has demonstrated remarkable outcomes when compared to conventional treatments in the management of recurrent and refractory brain tumors. However, in BNCT of brain tumors, the blood-brain barrier is a main stumbling block for restricting the transport of boron drugs to brain tumors, while the tumor targeting and retention of boron drugs also affect the BNCT effect. This review focuses on the recent development of strategies for delivering boron drugs crossing the blood-brain barrier and targeting brain tumors, providing new insights for the development of efficient boron drugs for the treatment of brain tumors.

In Vivo Application of Carboranes for Boron Neutron Capture Therapy (BNCT): Structure, Formulation and Analytical Methods for Detection.

Carboranes have emerged as one of the most promising boron agents in boron neutron capture therapy (BNCT). In this context, in vivo studies are particularly relevant, since they provide qualitative and quantitative information about the biodistribution of these molecules, which is of the utmost importance to determine the efficacy of BNCT, defining their localization and (bio)accumulation, as well as their pharmacokinetics and pharmacodynamics. First, we gathered a detailed list of the carboranes used for in vivo studies, considering the synthesis of carborane derivatives or the use of delivery system such as liposomes, micelles and nanoparticles. Then, the formulation employed and the cancer model used in each of these studies were identified. Finally, we examined the analytical aspects concerning carborane detection, identifying the main methodologies applied in the literature for ex vivo and in vivo analysis. The present work aims to identify the current strengths and weakness of the use of carboranes in BNCT, establishing the bottlenecks and the best strategies for future applications.

Acral cutaneous malignant melanoma treated with linear accelerator-based boron neutron capture therapy system: a case report of first patient.

This study reports the first patient treatment for cutaneous malignant melanoma using a linear accelerator-based boron neutron capture therapy (BNCT) system. A single-center open-label phase I clinical trial had been conducted using the system since November 2019. A patient with a localized node-negative acral malignant melanoma and the largest diameter of the tumor ≤ 15 cm who refused primary surgery and chemotherapy was enrolled. After administering boronophenylalanine (BPA), a single treatment of BNCT with the maximum dose of 18 Gy-Eq delivered to the skin was performed. The safety and efficacy of the accelerator-based BNCT system for treating localized cutaneous malignant melanoma were evaluated. The first patient with cutaneous malignant melanoma in situ on the second finger of the left hand did not develop dose-limiting toxicity in the clinical trial. After BNCT, the treatment efficacy was gradually observed, and the patient achieved PR within 6 months and CR within 12 months. Moreover, during the follow-up period of 12 months after BNCT, the patient did not exhibit a recurrence without any treatment-related grade 2 or higher adverse events. Although grade 1 adverse events of dermatitis, dry skin, skin hyperpigmentation, edema, nausea, and aching pain were noted in the patient, those adverse events were relieved without any treatment. This case report shows that the accelerator-based BNCT may become a promising treatment modality for cutaneous malignant melanoma. We expect further clinical trials to reveal the efficacy and safety of the accelerator-based BNCT for cutaneous malignant melanoma.