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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., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.)

Simple Summary: Many boron-containing compounds have been synthesized and proposed as boron-delivery agents for boron neutron capture therapy for cancers, including brain tumors and melanomas. However, only a few have been investigated in clinical studies, leaving their potential efficacy for cancer treatment unknown. With the recent availability of accelerator-based neutron sources, clinical trials are underway using the boronated amino acid (L)-4-hydroxyboryl phenylalanine. Simultaneously, there is renewed interest in the development of multi-functional boron-delivery agents for cancer diagnosis and treatment. Promising agents can deliver therapeutic amounts of boron into tumor cells with high specificity and low toxicity. Among the different classes of boron-containing compounds, peptide-, porphyrin-, liposome-, and nanoparticle-based-delivery agents are the most promising due to their tumor-targeting and concurrent imaging abilities. A systematic and comparative evaluation of these agents in clinical trials would allow the determination of their full potential for cancer treatment. Boron neutron capture therapy (BNCT) is a binary cancer treatment that involves the irradiation of 10B-containing tumors with low-energy neutrons (thermal or epithermal). The alpha particles and recoiling Li nuclei that are produced in the 10B-capture nuclear reaction are high-linear-energy transfer particles that destroy boron-loaded tumor cells; therefore, BNCT has the potential to be a localized therapeutic modality. Two boron-delivery agents have been used in clinical trials of BNCT in patients with malignant brain tumors, cutaneous melanoma, or recurrent tumors of the head and neck region, demonstrating the potential of BNCT in the treatment of difficult cancers. A variety of potentially highly effective boron-delivery agents have been synthesized in the past four decades and tested in cells and animal models. These include boron-containing nucleosides, peptides, proteins, polyamines, porphyrins, liposomes, monoclonal antibodies, and nanoparticles of various types. The most promising agents are multi-functional boronated molecules and nanoparticles functionalized with tumor cell-targeting moieties that increase their tumor selectivity and contain a radiolabel or fluorophore to allow quantification of 10B-biodistribution and treatment planning. This review discusses multi-functional boron agents reported in the last decade, but their full potential can only be ascertained after their evaluation in BNCT clinical trials. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy is a unique form of adjuvant cancer therapy for various malignancies including malignant gliomas. The conjugation of boron compounds and human serum albumin (HSA)-a carrier protein with a long plasma half-life-is expected to extend systemic circulation of the boron compounds and increase their accumulation in human glioma cells. We report on the synthesis of fluorophore-labeled homocystamide conjugates of human serum albumin and their use in thiol-'click' chemistry to prepare novel multimodal boronated albumin-based theranostic agents, which could be accumulated in tumor cells. The novelty of this work involves the development of the synthesis methodology of albumin conjugates for the imaging-guided boron neutron capture therapy combination. Herein, we suggest using thenoyltrifluoroacetone as a part of an anticancer theranostic construct: approximately 5.4 molecules of thenoyltrifluoroacetone were bound to each albumin. Along with its beneficial properties as a chemotherapeutic agent, thenoyltrifluoroacetone is a promising magnetic resonance imaging agent. The conjugation of bimodal HSA with undecahydro- closo -dodecaborate only slightly reduced human glioma cell line viability in the absence of irradiation (~30 μM of boronated albumin) but allowed for neutron capture and decreased tumor cell survival under epithermal neutron flux. The simultaneous presence of undecahydro- closo -dodecaborate and labeled amino acid residues (fluorophore dye and fluorine atoms) in the obtained HSA conjugate makes it a promising candidate for the combination imaging-guided boron neutron capture therapy.

Simple Summary: BNCT is a biologically targeted, densely ionizing form of radiation therapy that allows for increased tumor cell kill, while reducing toxicity to surrounding normal tissues. Although BNCT has been investigated in the treatment of head and neck cancers and recurrent brain tumors, its applicability to breast cancer has not been previoulsy investigated. In this review we discuss the physical and biological properties of various boronated compounds, and advantages and challenges associated with the potential use of BNCT in the treatment of breast cancer. BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states. [ABSTRACT FROM AUTHOR]

Boron-neutron capture therapy (BNCT) is an attractive technique for cancer treatment. As such, α, α-cycloalkyl amino acids containing thiododecaborate ([BH]-S-) units were designed and synthesized as novel boron delivery agents for BNCT. In the present study, new thiododecaborate α, α-cycloalkyl amino acids were synthesized, and biological evaluation of the boron compounds as boron carrier for BNCT was carried out. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is radiotherapy that depends on a nuclear reaction between boron-10 (10B) and neutrons. The neutron source has been changing from nuclear reactors to accelerators. Current BNCT using boronophenylalanine (BPA) as the boron compound has been shown to markedly reduce tumor sizes when used to treat recurrent head and neck cancer (HNC); however, early recurrence has been reported. Ultrasound, a safe diagnostic method, in combination with microbubbles, is expected to promote the uptake of BPA into tumor cells. Ultrasound also has the ability to increase the sensitivity of cancer cells to radiotherapy. Therefore, the combination of ultrasound needs to be promoted in order to improve the antitumor efficacy of BNCT for HNC. Boron neutron capture therapy (BNCT) is radiotherapy in which a nuclear reaction between boron-10 (10B) in tumor cells and neutrons produces alpha particles and recoiling 7Li nuclei with an extremely short range, leading to the destruction of the tumor cells. Although the neutron source has traditionally been a nuclear reactor, accelerators to generate neutron beams have been developed and commercialized. Therefore, this treatment will become more widespread. Recurrent head and neck cancer (HNC) close to the body surface is considered a candidate for BNCT using the boron compound boronophenylalanine (BPA) and has been found to be highly responsive to this treatment. However, some cases recur early after the completion of the treatment, which needs to be addressed. Ultrasound is a highly safe diagnostic method. Ultrasound with microbubbles is expected to promote the uptake of BPA into tumor cells. Ultrasound also has the ability to improve the sensitivity of tumor cells to radiotherapy. In addition, high-intensity focused ultrasound may improve the efficacy of BNCT via its thermal and mechanical effects. This review is not systematic but outlines the current status of BPA-based BNCT and proposes plans to reduce the recurrence rate of HNC after BNCT in combination with ultrasound. [ABSTRACT FROM AUTHOR]

Abstract The development of new accelerators has given a new impetus to the development of new drugs and treatment technologies using boron neutron capture therapy (BNCT). We analyzed the current status and future directions of BNCT for cancer treatment, as well as the main issues related to its introduction. This review highlights the principles of BNCT and the key milestones in its development: new boron delivery drugs and different types of charged particle accelerators are described; several important aspects of BNCT implementation are discussed. BCNT could be used alone or in combination with chemotherapy and radiotherapy, and it is evaluated in light of the outlined issues. For the speedy implementation of BCNT in medical practice, it is necessary to develop more selective boron delivery agents and to generate an epithermal neutron beam with definite characteristics. Pharmacological companies and research laboratories should have access to accelerators for large‐scale screening of new, more specific boron delivery agents.

Given the renewed interest in boron neutron capture therapy (BNCT) and the intensified search for improved boron carriers, as well as the difficulties of coherently comparing the carriers described so far, it seems necessary to define a basic set of assays and standardized methods to be used in the early stages of boron carrier development in vitro. The selection of assays and corresponding methods is based on the practical experience of the authors and is certainly not exhaustive, but open to discussion. The proposed tests/characteristics: Solubility, lipophilicity, stability, cytotoxicity, and cellular uptake apply to both low molecular weight (up to 500 Da) and high molecular weight (5000 Da and more) boron carriers. However, the specific methods have been selected primarily for low molecular weight boron carriers; in the case of high molecular weight compounds, some of the methods may need to be adapted. [ABSTRACT FROM AUTHOR]

The development of new boron-delivery agents is a high priority for improving the effectiveness of boron neutron capture therapy. In the present study, 1-amino-3-borono-cyclopentanecarboxylic acid (cis-ABCPC) as a mixture of its L- and D-enantiomers was evaluated in vivo using the B16 melanoma model for the human tumor and the F98 rat glioma as a model for human gliomas. A secondary ion mass spectrometry (SIMS) based imaging instrument, CAMECA IMS 3F SIMS Ion Microscope, was used for quantitative imaging of boron at 500 nm spatial resolution. Both in vivo and in vitro studies in melanoma models demonstrated that boron was localized in the cytoplasm and nuclei with some cell-to-cell variability. Uptake of cis-ABCPC in B16 cells was time dependent with a 7.5:1 partitioning ratio of boron between cell nuclei and the nutrient medium after 4 hrs. incubation. Furthermore, cis-ABCPC delivered boron to cells in all phases of the cell cycle, including S-phase. In vivo SIMS studies using the F98 rat glioma model revealed an 8:1 boron partitioning ratio between the main tumor mass and normal brain tissue with a 5:1 ratio between infiltrating tumor cells and contiguous normal brain. Since cis-ABCPC is water soluble and can cross the blood-brain-barrier via the L-type amino acid transporters (LAT), it may accumulate preferentially in infiltrating tumor cells in normal brain due to up-regulation of LAT in high grade gliomas. Once trapped inside the tumor cell, cis-ABCPC cannot be metabolized and remains either in a free pool or bound to cell matrix components. The significant improvement in boron uptake by both the main tumor mass and infiltrating tumor cells compared to those reported in animal and clinical studies of p-boronophenylalanine strongly suggest that cis-ABCPC has the potential to become a novel new boron delivery agent for neutron capture therapy of gliomas and melanomas.

The efficiency of boron neutron capture therapy (BNCT) for malignant gliomas depends on the selective and absolute accumulation of (10)B atoms in tumor tissues. Only two boron compounds, BPA and BSH, currently can be used clinically. However, the detailed distributions of these compounds have not been determined. Here we used secondary ion mass spectrometry (SIMS) to determine the histological distribution of (10)B atoms derived from the boron compounds BSH and BPA. C6 tumor-bearing rats were given 500 mg/kg of BPA or 100 mg/kg of BSH intraperitoneally; 2.5 h later, their brains were sectioned and subjected to SIMS. In the main tumor mass, BPA accumulated heterogeneously, while BSH accumulated homogeneously. In the peritumoral area, both BPA and BSH accumulated measurably. Interestingly, in this area, BSH accumulated distinctively in a diffuse manner even 800 microm distant from the interface between the main tumor and normal brain. In the contralateral brain, BPA accumulated measurably, while BSH did not. In conclusion, both BPA and BSH each have advantages and disadvantages. These compounds are considered to be essential as boron delivery agents independently for clinical BNCT. There is some rationale for the simultaneous use of both compounds in clinical BNCT for malignant gliomas.

In this article we report the physicochemical characterization of cationic liposomes loaded with orthocarborane and two of its sugar-containing derivatives. Carboranes are efficient boron delivery agents in boron neutron capture therapy, an anti-cancer treatment based on neutron absorption by 10B nuclei. Cationic liposomes were prepared using the positively charged DOTAP and the zwitterionic DOPE, as a helper lipid. These liposomes are currently used in gene therapy for their ability in targeting the cell nucleus; therefore they can be considered appropriate vectors for boron neutron capture therapy, in the quest of reducing the high boron amount that is necessary for successful cancer treatment. Boron uptake was determined by an original in situ method, based on neutron absorption. The structural properties of the loaded liposomes were studied in detail by the combined use of small angle x-ray scattering and small angle neutron scattering. These techniques established the global shape and size of liposomes and their bilayer composition. The results were discussed in term of molecular properties of the hosted drugs. Differences found in the insertion modality were correlated with the preparation procedure or with the specific shape and lipophilic-hydrophilic balance of each carborane.

The purpose of the present study was to evaluate both in vitro and in vivo a series of boron-containing nucleosides that potentially could be used as delivery agents for neutron capture therapy. The rationale for their synthesis was based on the fact that proliferating neoplastic cells have increased requirements for nucleic acid precursors, and, therefore, they should preferentially localize in the tumor. A series of 3-carboranlyalkyl thymidine analogs has been synthesized and a subset, designated N4, N5, and N7, and the corresponding 3-dihydroxypropyl derivatives, designated N4-2OH, N5-2OH, and N7-2OH, have been selected for evaluation. Using these compounds as substrates for recombinant human thymidine kinase-1 and the mitochondrial isoenzyme thymidine kinase-2, the highest phosphorylation levels relative to thymidine were seen with N5 and the corresponding dihydroxypropyl analog N5-2OH. In contrast, N4, N4-OH, N7, and N7-OH had substantially lower phosphorylation levels. To compare compounds with high and low thymidine kinase-1 substrate activity, N5 and N7 and the corresponding dihydroxypropyl derivatives were selected for evaluation of their cellular toxicity, uptake and retention by the F98 rat glioma, human MRA melanoma, and murine L929 cell lines, all of which are thymidine kinase-1(+), and a mutant L929 cell line that is thymidine kinase-1(-). N5-2OH was the least toxic (IC50, 43-70 microm), and N7 and N7-2OH were the most toxic (IC50, 18-49 microm). The highest boron uptake was seen with N7-2OH by the MRA 27 melanoma and L929 wild-type (wt) cell lines. The highest retention was seen with L929 (wt) cells, and this ranged from 29% for N5-2OH to 46% for N7. Based on the in vitro toxicity and uptake data, N5-2OH was selected for in vivo biodistribution studies either in rats bearing intracerebral implants of the F98 glioma or in mice bearing either s.c. or intracerebral implants of L929 (wt) tumors. At 2.5 hours after convection-enhanced delivery, the boron values for the F98 glioma and normal brain were 16.2 +/- 2.3 and 2.2 microg/g, respectively, and the tumor to brain ratio was 8.5. Boron values at 4 hours after convection-enhanced delivery of N5-2OH to mice bearing intracerebral implants of L929 (wt) or L929 thymidine kinase-1(-) tumors were 39.8 +/- 10.8 and 12.4 +/- 1.6 microg/g, respectively, and the corresponding normal brain values were 4.4 and 1.6 microg/g, thereby indicating that there was selective retention by the thymidine kinase-1(+) tumors. Based on these favorable in vitro and in vivo data, neutron capture therapy studies will be initiated using N5-2OH in combination with two non-cell cycle dependent boron delivery agents, boronophenylalanine and sodium borocaptate.

Interest in the design of boronated amino acids has emerged, partly due to the utilization of boronophenylalanine (BPA), one of the two agents employed in clinical Boron Neutron Capture Therapy (BNCT). The boronated amino acids synthesized thus far for BNCT investigations can be classified into two categories based on the source of boron: boronic acids or carboranes. Amino acid-based boron carriers, employed in the context of BNCT treatment, demonstrate significant potential in the treatment of challenging tumors, such as those located in the brain. This review aims to shed light on the developmental journey and challenges encountered over the years in the field of amino acid-based boron delivery compound development. The primary focus centers on the utilization of the large amino acid transporter 1 (LAT1) as a target for boron carriers in BNCT. The development of efficient carriers remains a critical objective, addressing challenges related to tumor specificity, effective boron delivery, and rapid clearance from normal tissue and blood. LAT1 presents an intriguing and promising target for boron delivery, given its numerous characteristics that make it well suited for drug delivery into tumor tissues, particularly in the case of brain tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we explored new methods for treating aggressive brain tumors and, particularly, high-grade gliomas. These types of tumors are notoriously difficult to treat effectively; therefore, we focused on a procedure called boron neutron capture therapy (BNCT). BNCT is a particle beam therapy that can selectively destroy tumor cells. However, boronophenylalanine (BPA), a boron compound currently used in this therapy, has limitations. We tested a new compound, boron-conjugated 4-iodophenylbutanamide (BC-IP) and found that even though it does not carry as much boron into the cells as BPA, it remains in the cells longer, which is beneficial for treatment. We also tested BNCT mediated by BC-IP in rats with gliomas and found that it prolonged survival compared to controls (not treated animals and neutrons only). Our work could potentially improve the treatment options for patients with high-grade gliomas. However, further research is required to understand how to best use this new compound for patient benefits. High-grade gliomas present a significant challenge in neuro-oncology because of their aggressive nature and resistance to current therapies. Boron neutron capture therapy (BNCT) is a potential treatment method; however, the boron used by the carrier compounds—such as 4-borono-L-phenylalanine (L-BPA)—have limitations. This study evaluated the use of boron-conjugated 4-iodophenylbutanamide (BC-IP), a novel boron compound in BNCT, for the treatment of glioma. Using in vitro drug exposure experiments and in vivo studies, we compared BC-IP and BPA, with a focus on boron uptake and retention characteristics. The results showed that although BC-IP had a lower boron uptake than BPA, it exhibited superior retention. Furthermore, despite lower boron accumulation in tumors, BNCT mediated by BC-IP showed significant survival improvement in glioma-bearing rats compared to controls (not treated animals and neutrons only). These results suggest that BC-IP, with its unique properties, may be an alternative boron carrier for BNCT. Further research is required to optimize this potential treatment modality, which could significantly contribute to advancing the treatment of high-grade gliomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy. It combines preferential boron accumulation in tumors and neutron irradiation. Throughout the history of BNCT, huge efforts have been made on the development of more efficient boron-carrying agents. We analyzed, in this review, those articles published between 2020 and 2023 reporting new boron compounds and strategies that were proved therapeutically useful in in vitro and/or in vivo radiobiological studies, a critical step for translation to a clinical setting. We also explored new pathologies that could potentially be treated with BNCT. We analyzed examples of newly studied theranostic boron agents that could improve significantly BNCT therapeutic effect. These radiobiological advances intend to solve those limitations and questions that arise during patient treatment in the clinical field, with BNCT and other therapies. An active communication between clinicians, radiobiologists, and all disciplines will improve BNCT for cancer patients, in a cost- and time-effective way. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy. It combines preferential boron accumulation in tumors and neutron irradiation. The recent initiation of BNCT clinical trials employing hospital-based accelerators rather than nuclear reactors as the neutron source will conceivably pave the way for new and more numerous clinical trials, leading up to much-needed randomized trials. In this context, it would be interesting to consider the implementation of new boron compounds and strategies that will significantly optimize BNCT. With this aim in mind, we analyzed, in this review, those articles published between 2020 and 2023 reporting new boron compounds and strategies that were proved therapeutically useful in in vitro and/or in vivo radiobiological studies, a critical step for translation to a clinical setting. We also explored new pathologies that could potentially be treated with BNCT and newly developed theranostic boron agents. All these radiobiological advances intend to solve those limitations and questions that arise during patient treatment in the clinical field, with BNCT and other therapies. In this sense, active communication between clinicians, radiobiologists, and all disciplines will improve BNCT for cancer patients, in a cost- and time-effective way. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is an innovative radiation therapy that shows promise in treating certain types of cancer. Recent advancements in BNCT have focused on developing compact neutron source devices and more effective boron agents in mainland China. This paper highlights the successful transition of two compact neutron source devices from research to clinical trials, with plans underway for their registration as medical devices. Moreover, accelerator-based neutron source devices in construction and the development of boron agents are introduced. The challenges facing BNCT in practice in mainland China as a widely accepted and implemented cancer treatment are analyzed. Boron neutron capture therapy (BNCT) is a promising cancer treatment modality that combines targeted boron agents and neutron irradiation to selectively destroy tumor cells. In mainland China, the clinical implementation of BNCT has made certain progress, primarily driven by the development of compact neutron source devices. The availability, ease of operation, and cost-effectiveness offered by these compact neutron sources make BNCT more accessible to cancer treatment centers. Two compact neutron sources, one being miniature reactor-based (IHNI-1) and the other one being accelerator-based (NeuPex), have entered the clinical research phase and are planned for medical device registration. Moreover, several accelerator-based neutron source devices employing different technical routes are currently under construction, further expanding the options for BNCT implementation. In addition, the development of compact neutron sources serves as an experimental platform for advancing the development of new boron agents. Several research teams are actively involved in the development of boron agents. Various types of third-generation boron agents have been tested and studied in vitro and in vivo. Compared to other radiotherapy therapies, BNCT in mainland China still faces specific challenges due to its limited clinical trial data and its technical support in a wide range of professional fields. To facilitate the widespread adoption of BNCT, it is crucial to establish relevant technical standards for neutron devices, boron agents, and treatment protocols. [ABSTRACT FROM AUTHOR]

The aim of this study was to create molecularly imprinted polymers (MIPs) that are specific towards 4-borono-L-phenylalanine (BPA) to serve as boron compound carriers. The honeycomb-like MIPs were characterized in the matter of adsorption properties, morphology, structure, and cytotoxicity towards A549 and V79-4 cell lines. The honeycomb-like MIP composed from methacrylic acid and ethylene glycol dimethacrylate was characterized by a binding capacity of 330.4 ± 4.6 ng g−1 and an imprinting factor of 2.04, and its ordered, porous morphology was confirmed with scanning electron microscopy. The theoretical analysis revealed that the coexistence of different anionic forms of the analyte in basic solution might lower the binding capacity of the MIP towards BPA. The release profiles from the model phosphate buffer saline showed that only 0 to 4.81% of BPA was released from the MIP within the time frame of two hours, furthermore, the obtained material was considered non-cytotoxic towards tested cell lines. The results prove that MIPs can be considered as effective BPA delivery systems for biomedical applications and should be investigated in further studies. [ABSTRACT FROM AUTHOR]

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is the most aggressive type of astrocytic glioma. GBMs are diffuse infiltrating tumours that present with extensive hypoxia and genetic heterogeneity amongst other features that have rendered treatment strategies ineffectual, despite recent advances in multimodality therapy regimens. The prognosis remains poor and median survival is less than 17 months using adjuvant chemotherapy and X-ray external radiotherapy. Therefore, strategies should be investigated to target complications associated with this malignancy. A targeted approach with high linear energy transfer particles could address infiltration and cellular aggressiveness (e.g., heterogeneity, hypoxia, and intrinsic radiosensitivity) issues, respectively. Boron neutron capture therapy (BNCT), a biochemically-targeted modality, proposes an attractive solution for GBM. A hybrid computational framework was previously developed by our group to quantify the efficacy of BNCT at its current status of development for a simplified GBM model. This work has expanded the framework to a semi-realistic GBM model with heterogeneous radiosensitivity and anisotropic microscopic extensions; moreover, the neutron beam model and neutron transport components have undergone substantial improvements. Background: Glioblastomas (GBMs) are notorious for their aggressive features, e.g., intrinsic radioresistance, extensive heterogeneity, hypoxia, and highly infiltrative behaviours. The prognosis has remained poor despite recent advances in systemic and modern X-ray radiotherapy. Boron neutron capture therapy (BNCT) represents an alternative radiotherapy technique for GBM. Previously, a Geant4 BNCT modelling framework was developed for a simplified model of GBM. Purpose: The current work expands on the previous model by applying a more realistic in silico GBM model with heterogeneous radiosensitivity and anisotropic microscopic extensions (ME). Methods: Each cell within the GBM model was assigned an α / β value associated with different GBM cell lines and a 10 B concentration. Dosimetry matrices corresponding to various MEs were calculated and combined to evaluate cell survival fractions (SF) using clinical target volume (CTV) margins of 2.0 & 2.5 cm. SFs for the BNCT simulation were compared with external X-ray radiotherapy (EBRT) SFs. Results: The SFs within the beam region decreased by more than two times compared to EBRT. It was demonstrated that BNCT results in markedly reduced SFs for both CTV margins compared to EBRT. However, the SF reduction as a result of the CTV margin extension using BNCT was significantly lower than using X-ray EBRT for one MEP distribution, while it remained similar for the other two MEP models. Conclusions: Although the efficiency of BNCT in terms of cell kill is superior to EBRT, the extension of the CTV margin by 0.5 cm may not increase the BNCT treatment outcome significantly. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a binary therapeutic technique employing a boron agent to be delivered to the tumor site followed by the irradiation of neutrons. Biofunctional molecules/nanoparticles labeled with F-18 can provide an initial pharmacokinetic profile of patients to guide the subsequent treatment planning procedure of BNCT. Borono phenylalanine (BPA), recognized by the l-type amino acid transporter, can cross the blood-brain barrier and be accumulated in gliomas. The radiofluoro BNCT agents are reviewed by considering (1) less cytotoxicity, (2) diagnosing and therapeutic purposes, (3) aqueous solubility and extraction route, as well as (4), the trifluoroborate effect. A trifluoroborate-containing amino acid such as fluoroboronotyrosine (FBY) represents an example with both functionalities of imaging and therapeutics. Comparing with the insignificant cytotoxicity of clinical BPA with IC50 > 500 μM, FBY also shows minute toxicity with IC50 > 500 μM. [18F]FBY is a potential diagnostic agent for its tumor to normal accumulation (T/N) ratio, which ranges from 2.3 to 24.5 from positron emission tomography, whereas the T/N ratio of FBPA is greater than 2.5. Additionally, in serving as a BNCT therapeutic agent, the boron concentration of FBY accumulated in gliomas remains uncertain. The solubility of 3-BPA is better than that of BPA, as evidenced by the cerebral dose of 3.4%ID/g vs. 2.2%ID/g, respectively. While the extraction route of d-BPA differs from that of BPA, an impressive T/N ratio of 6.9 vs. 1.5 is noted. [18F]FBPA, the most common clinical boron agent, facilitates the application of BPA in clinical BNCT. In addition to [18F]FBY, [18F] trifluoroborated nucleoside analog obtained through 1,3-dipolar cycloaddition shows marked tumoral uptake of 1.5%ID/g. Other examples using electrophilic and nucleophilic fluorination on the boron compounds are also reviewed, including diboronopinacolone phenylalanine and nonsteroidal anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Usually, for dose planning in radiotherapy, the tumor is delimited as a volume on the image of the patient together with other clinical considerations based on populational evidence. However, the same prescription dose can provide different results, depending on the patient. Unfortunately, the biological aspects of the tumor are hardly considered in dose planning. Boron Neutron Capture Radiotherapy enables targeted treatment by incorporating boron-10 at the cellular level and irradiating with neutrons of a certain energy so that they produce nuclear reactions locally and almost exclusively damage the tumor cell. This technique is not new, but modern neutron generators and more efficient boron carriers have reactivated the clinical interest of this technique in the pursuit of more precise treatments. In this work, we review the latest technological facilities and future possibilities for the clinical implementation of BNCT and for turning it into a personalized therapy. Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (10B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what is usual in radiotherapy, BNCT proposes cell-tailored treatment planning rather than to the tumor mass. The success of BNCT depends mainly on the sufficient spatial biodistribution of 10B located around or within neoplastic cells to produce a high-dose gradient between the tumor and healthy tissue. However, it is not yet possible to precisely determine the concentration of 10B in a specific tissue in real-time using non-invasive methods. Critical issues remain to be resolved if BNCT is to become a valuable, minimally invasive, and efficient treatment. In addition, functional imaging technologies, such as PET, can be applied to determine biological information that can be used for the combined-modality radiotherapy protocol for each specific patient. Regardless, not only imaging methods but also proteomics and gene expression methods will facilitate BNCT becoming a modality of personalized medicine. This work provides an overview of the fundamental principles, recent advances, and future directions of BNCT as cell-targeted cancer therapy for personalized radiation treatment. [ABSTRACT FROM AUTHOR]

Boron compounds now have many applications in a number of fields, including Medicinal Chemistry. Although the uses of boron compounds in pharmacological science have been recognized several decades ago, surprisingly few are found in pharmaceutical drugs. The boron-containing compounds epitomize a new class for medicinal chemists to use in their drug designs. Carboranes are a class of organometallic compounds containing carbon (C), boron (B), and hydrogen (H) and are the most widely studied boron compounds in medicinal chemistry. Additionally, other boron-based compounds are of great interest, such as dodecaborate anions, metallacarboranes and metallaboranes. The boron neutron capture therapy (BNCT) has been utilized for cancer treatment from last decade, where chemotherapy and radiation have their own shortcomings. However, the improvement in the already existing (BPA and/or BSH) localized delivery agents or new tumor-targeted compounds are required before realizing the full clinical potential of BNCT. The work outlined in this short review addresses the advancements in boron containing compounds. Here, we have focused on the possible clinical implications of the new and improved boron-based biologically active compounds for BNCT that are reported to have in vivo and/or in vitro efficacy. [ABSTRACT FROM AUTHOR]

Background: Boron neutron capture therapy (BNCT) is a unique particle radiation therapy based on the nuclear capture reactions in boron-10. We developed a novel boron-10 containing sodium borocaptate (BSH) derivative, 1-amino-3-fluorocyclobutane-1-carboxylic acid (ACBC)-BSH. ACBC is a tumor selective synthetic amino acid. The purpose of this study was to assess the biodistribution of ACBC-BSH and its therapeutic efficacy following Boron Neutron Capture Therapy (BNCT) of the F98 rat glioma.Methods: We evaluated the biodistribution of three boron-10 compounds, ACBC-BSH, BSH and boronophenylalanine (BPA), in vitro and in vivo, following intravenous (i.v.) administration and intratumoral (i.t.) convection-enhanced delivery (CED) in F98 rat glioma bearing rats. For BNCT studies, rats were stratified into five groups: untreated controls, neutron-irradiation controls, BNCT with BPA/i.v., BNCT with ACBC-BSH/CED, and BNCT concomitantly using BPA/i.v. and ACBC-BSH/CED.Results: In vitro, ACBC-BSH attained higher cellular uptake F98 rat glioma cells compared with BSH. In vivo biodistribution studies following i.v. administration and i.t. CED of ACBC-BSH attained significantly higher boron concentrations than that of BSH, but much lower than that of BPA. However, following convection enhanced delivery (CED), ACBC-BSH attained significantly higher tumor concentrations than BPA. The i.t. boron-10 concentrations were almost equal between the ACBC-BSH/CED group and BPA/i.v. group of rats. The tumor/brain boron-10 concentration ratio was higher with ACBC-BSH/CED than that of BPA/i.v. group. Based on these data, BNCT studies were carried out in F98 glioma bearing rats using BPA/i.v. and ACBC-BSH/CED as the delivery agents. The corresponding mean survival times were 37.4 ± 2.6d and 44.3 ± 8.0d, respectively, and although modest, these differences were statistically significant.Conclusions: Our findings suggest that further studies are warranted to evaluate ACBC-BSH/CED as a boron delivery agent. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors. Although a variety of GBMs is initially susceptible to chemotherapy, the development of multi-drug resistance and recurrence is frequent. Therefore, there is an urgent need for more efficient treatment modalities for GBM. Boron neutron capture therapy (BNCT) is a cancer therapy based on the potential of 10B atoms to produce α particles that cross tissues in which the 10B accumulates without damaging the surrounding healthy tissues after irradiation with low energy thermal neutrons. The aim of our study was to assess that the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative could be good candidates for dual anti-cancer treatment (chemotherapy + BNCT). Our results strongly suggest that these small molecules, in particular [8,8′-I2-o-COSAN]−, are serious candidates to be taken into account for BNCT now that the accelerator-based neutron source facilities are more accessible, providing an alternative treatment for resistant glioblastoma. Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8′-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8′-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8′-I2-o-COSAN]−, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Accelerator-based boron neutron capture therapy (BNCT) has opened up new perspectives in increasing cancer treatment efficacy, including malignant brain tumors and particularly glioblastoma. We studied dosimetry control optimization, neutron beam parameter adjustment, and two boron compound combinations (along with single and double irradiation regimens) to assess safety and increase therapy efficacy, using a U87MG xenotransplant immunodeficient mouse model. In two sets of experiments, we achieved increases in tumor-growth inhibition (to 80–83%), a neutron capture therapy ratio of 2:1 (two times higher neutron capture therapy efficacy than neutron irradiation without boron), and increases in animal life expectancy, from 9 to 107 days, by treatment parameter adjustment. These results will contribute to the development of clinical-trial protocols for accelerator-based BNCT and further innovations in this cancer treatment method. (1) Background: Developments in accelerator-based neutron sources moved boron neutron capture therapy (BNCT) to the next phase, where new neutron radiation parameters had to be studied for the treatment of cancers, including brain tumors. We aimed to further improve accelerator-BNCT efficacy by optimizing dosimetry control, beam parameters, and combinations of boronophenylalanine (BPA) and sodium borocaptate (BSH) administration in U87MG xenograft-bearing immunodeficient mice with two different tumor locations. (2) Methods: The study included two sets of experiments. In Experiment #1, BPA only and single or double irradiation in higher doses were used, while, in Experiment #2, BPA and BSH combinations and single or double irradiation with dosage adjustment were analyzed. Mice without treatment or irradiation after BPA or BPA+BSH injection were used as controls. (3) Results: Irradiation parameter adjustment and BPA and BSH combination led to 80–83% tumor-growth inhibition index scores, irradiation:BNCT ratios of 1:2, and increases in animal life expectancy from 9 to 107 days. (4) Conclusions: Adjustments in dosimetry control, calculation of irradiation doses, and combined use of two 10B compounds allowed for BNCT optimization that will be useful in the development of clinical-trial protocols for accelerator-based BNCT. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is becoming one of the most promising radiotherapies for aggressive cancers, but the detailed cellular mechanisms of BNCT remain largely underexplored. Solid tumors are composed of heterogeneous cell populations, which create a 3-dimensional complicated microenvironment for tumor progression. To recapture the influences of the microenvironment on BNCT efficacy, we applied a self-assembly 3D cell culture system with two different types of pancreatic cancer cells. In contrast to previous findings with γ-ray exposure, we found that the 3D architecture of pancreatic tumor can facilitate the susceptibility of cancer cells to BNCT, as compared to 2D tissue structure; a computer simulation model was established to further confirm this unexpected finding. These outcomes can contribute to better understanding of the radiobiology of BNCT, and the developed models may facilitate the recent development in personalized radiotherapy. Pancreatic cancer is a leading cause of cancer death, and boron neutron capture therapy (BNCT) is one of the promising radiotherapy techniques for patients with pancreatic cancer. In this study, we evaluated the biological effectiveness of BNCT at multicellular levels using in vitro and in silico models. To recapture the phenotypic characteristic of pancreatic tumors, we developed a cell self-assembly approach with human pancreatic cancer cells Panc-1 and BxPC-3 cocultured with MRC-5 fibroblasts. On substrate with physiological stiffness, tumor cells self-assembled into 3D spheroids, and the cocultured fibroblasts further facilitated the assembly process, which recapture the influence of tumor stroma. Interestingly, after 1.2 MW neutron irradiation, lower survival rates and higher apoptosis (increasing by 4-fold for Panc-1 and 1.5-fold for BxPC-3) were observed in 3D spheroids, instead of in 2D monolayers. The unexpected low tolerance of 3D spheroids to BNCT highlights the unique characteristics of BNCT over conventional radiotherapy. The uptake of boron-containing compound boronophenylalanine (BPA) and the alteration of E-cadherin can partially contribute to the observed susceptibility. In addition to biological effects, the probability of induced α-particle exposure correlated to the multicellular organization was speculated to affect the cellular responses to BNCT. A Monte Carlo (MC) simulation was also established to further interpret the observed survival. Intracellular boron distribution in the multicellular structure and related treatment resistance were reconstructed in silico. Simulation results demonstrated that the physical architecture is one of the essential factors for biological effectiveness in BNCT, which supports our in vitro findings. In summary, we developed in vitro and in silico self-assembly 3D models to evaluate the effectiveness of BNCT on pancreatic tumors. Considering the easy-access of this 3D cell-assembly platform, this study may not only contribute to the current understanding of BNCT but is also expected to be applied to evaluate the BNCT efficacy for individualized treatment plans in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: We have developed a new boron compound for application in boron neutron capture therapy (BNCT) named boronophenylalanine–amide alkyl dodecaborate (BADB). It is characterized by a larger amount of 10B per molecule, linking boronphenylalanine (BPA) and dodecaborate, and we conducted various experiments on its efficacy. Its high accumulation at the cellular level made it a promising novel drug, but it did not sufficiently accumulate in brain tumor tissue when intravenously administered. However, in neutron irradiation experiments, the drug showed remarkably high compound biological effectiveness and significantly prolonged the survival time in rat brain tumor models. We confirmed the antitumor efficacy of BADB in BNCT and its additional efficacy when administered in combination with BPA. Though this drug showed poor results when administered as a single agent, it was superior to BPA alone when administered in combination with BPA, making it a drug that we have been waiting for in our clinical practice. Background: The development of effective boron compounds is a major area of research in the study of boron neutron capture therapy (BNCT). We created a novel boron compound, boronophenylalanine–amide alkyl dodecaborate (BADB), for application in BNCT and focused on elucidating how it affected a rat brain tumor model. Methods: The boron concentration of F98 rat glioma cells following exposure to boronophenylalanine (BPA) (which is currently being utilized clinically) and BADB was evaluated, and the biodistributions in F98 glioma-bearing rats were assessed. In neutron irradiation studies, the in vitro cytotoxicity of each boron compound and the in vivo corresponding therapeutic effect were evaluated in terms of survival time. Results: The survival fractions of the groups irradiated with BPA and BADB were not significantly different. BADB administered for 6 h after the termination of convection-enhanced delivery ensured the highest boron concentration in the tumor (45.8 μg B/g). The median survival time in the BADB in combination with BPA group showed a more significant prolongation of survival than that of the BPA group. Conclusion: BADB is a novel boron compound for BNCT that triggers a prolonged survival effect in patients receiving BNCT. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most lethal tumor among all cancers with a median overall survival of 14 months and to develop new effective therapies is an urgent issue. Boron Neutron Capture Therapy (BNCT) is a unique radiation therapy that uses boron compounds and thermal neutrons. This study is aimed to investigate whether glioma stem cells, which is resistant to chemo-radiation therapy, take up a boron compound, p-boronophenylalanine (BPA) or not. Both in vitro and in vivo studies, more glioma stem like cells took up BPA compared with the differentiated glioma cells and indicated that BNCT can target to kill GSCs and be an effective therapy for malignant glioma. As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5–9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2–4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT. [ABSTRACT FROM AUTHOR]