Incorporating boron distribution variations in microdosimetric kinetic model-based relative biological effectiveness calculations for boron neutron capture therapy.

This study introduces the MKM_B model, an approach derived from the MKM model, designed to evaluate the biological effectiveness of Boron Neutron Capture Therapy (BNCT) in the face of challenges from varying microscopic boron distributions. The model introduces a boron compensation factor, allowing for the assessment of compound Biological Effectiveness (CBE) values for different boron distributions. Utilizing the TOPAS simulation platform, the lineal energy spectrum of particles in BNCT was simulated, and the sensitivity of the MKM_B model to parameter variations and the influence of cell size on the model were thoroughly investigated. The CBE values for 10B-boronphenylalanine (BPA) and 10B-sodium (BSH) were determined to be 3.70 and 1.75, respectively. These calculations were based on using the nucleus radius of 2.5 µm and the cell radius of 5 µm while considering a 50% surviving fraction. It was observed that as cell size decreased, the CBE values for both BPA and BSH increased. Additionally, the model parameter rd was identified as having the most significant impact on CBE, with other parameters showing moderate effects. The development of the MKM_B model enables the accurate prediction of CBE under different boron distributions in BNCT. This model offers a promising approach to optimize treatment planning by providing increased accuracy in biological effectiveness.

Boron neutron capture therapy delays the decline in neurological function in a mouse model of metastatic spinal tumors.

Metastatic spinal tumors are increasingly prevalent due to advancements in cancer treatment, leading to prolonged survival rates. This rising prevalence highlights the need for developing more effective therapeutic approaches to address this malignancy. Boron neutron capture therapy (BNCT) offers a promising solution by delivering targeted doses to tumors while minimizing damage to normal tissue. In this study, we evaluated the efficacy and safety of BNCT as a potential therapeutic option for spine metastases in mouse models induced by A549 human lung adenocarcinoma cells. The animal models were randomly allocated into three groups: untreated (n = 10), neutron irradiation only (n = 9), and BNCT (n = 10). Each mouse was administered 4-borono-L-phenylalanine (250 mg/kg) intravenously, followed by measurement of boron concentrations 2.5 h later. Overall survival, neurological function of the hindlimb, and any adverse events were assessed post irradiation. The tumor-to-normal spinal cord and blood boron concentration ratios were 3.6 and 2.9, respectively, with no significant difference observed between the normal and compressed spinal cord tissues. The BNCT group exhibited significantly prolonged survival rates compared with the other groups (vs. untreated, p = 0.0015; vs. neutron-only, p = 0.0104, log-rank test). Furthermore, the BNCT group demonstrated preserved neurological function relative to the other groups (vs. untreated, p = 0.0004; vs. neutron-only, p = 0.0051, multivariate analysis of variance). No adverse events were observed post irradiation. These findings indicate that BNCT holds promise as a novel treatment modality for metastatic spinal tumors.

DNA-damage RBE assessment for combined boron and gadolinium neutron capture therapy.

PURPOSE: Neutron capture therapy (NCT) by 10B and 157Gd agents is a unique irradiation-based method which can be used to treat brain tumors. Current study aims to quantitatively evaluate the relative biological effectiveness (RBE) and dose distributions during the combined BNCT and GdNCT modalities through a hybrid Monte Carlo (MC) simulation approach. METHODS: Snyder head phantom as well as a cubic hypothetical tumor was at first modeled by Geant4 MC Code. Then, the energy spectra and dose distribution relevant to the released secondary particles during the combined Gd/BNCT were scored for different concentrations of 157Gd and 10B inside tumor volume. Finally, the scored energy spectra were imported to the MCDS code to estimate both RBESSB and RBEDSB values for different 157Gd concentrations. RESULTS: The results showed that combined Gd/BNCT increases the fluence-averaged RBESSB values by about 1.7 times when 157Gd concentration increments from 0 to 2000 µg/g for both considered cell oxygen levels (pO2 = 10% and 100%). Besides, a reduction of about 26% was found for fluence-averaged RBEDSB values with an increment of 157Gd concentration in tumor volume. CONCLUSION: From the results, it can be concluded that combined Gd/BNCT technique can improve tumor coverage with higher dose levels but in the expense of RBEDSB reduction which can affect the clinical efficacy of the NCT technique.

Neutron Capture Enhances Dose and Reduces Cancer Cell Viability in and out of Beam During Helium and Carbon Ion Therapy.

PURPOSE: Neutron capture enhanced particle therapy (NCEPT) is a proposed augmentation of charged particle therapy that exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with 2 different targeted neutron capture agents (NCAs). METHODS AND MATERIALS: Human glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a polymethyl methacrylate phantom either laterally adjacent to or within a 100 × 100 × 60 mm spread out Bragg peak (SOBP). The effect of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in 6 independent experiments. Neutron fluence within the phantom was characterized by quantifying the neutron activation of gold foil. RESULTS: Cells placed inside the treatment volume reached 10% survival by 2 Gy of carbon or 2 to 3 Gy of helium in the presence of NCAs compared with 5 Gy of carbon and 7 Gy of helium with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of carbon or helium (to the treatment volume), compared with no detectable effect on cells without NCA. The mean thermal neutron fluence at the center of the SOBP was approximately 2.2 × 109 n/cm2/Gy (relative biological effectiveness) for the carbon beam and 5.8 × 109 n/cm2/Gy (relative biological effectiveness) for the helium beam and gradually decreased in all directions. CONCLUSIONS: The addition of NCAs to cancer cells during carbon and helium beam irradiation has a measurable effect on cell survival and growth in vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumors, by targeting this dose to microinfiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumor tissue within the treatment volume, with a reduction in radiation doses to off-target tissue.

Experimental study on Compton camera for boron neutron capture therapy applications.

Boron neutron capture therapy (BNCT) is a high-dose-intensive radiation therapy that has gained popularity due to advancements in accelerator neutron sources. To determine the dose for BNCT, it is necessary to know the difficult-to-determine boron concentration and neutron fluence. To estimate this dose, we propose a method of measuring the prompt γ-rays (PGs) from the boron neutron capture reaction (BNCR) using a Compton camera. We performed a fundamental experiment to verify basic imaging performance and the ability to discern the PGs from 511 keV annihilation γ-rays. A Si/CdTe Compton camera was used to image the BNCR and showed an energy peak of 478 keV PGs, separate from the annihilation γ-ray peak. The Compton camera could visualize the boron target with low neutron intensity and high boron concentration. This study experimentally confirms the ability of Si/CdTe Compton cameras to image BNCRs.

Boron in cancer therapeutics: An overview.

Boron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1α, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies.

Next-Generation Boron Drugs and Rational Translational Studies Driving the Revival of BNCT.

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.

The effect of the boron-based gel on the treatment of diabetic foot ulcers: A prospective, randomized controlled trial.

BACKGROUND: Chronic ulcers represent impaired healing capacity with high mortality in the elderly or patients with systemic disorders such as diabetes. Boron is an effective agent in wound healing by promoting cell migration and proliferation and reducing inflammation in the wound area. This study aimed to evaluate the therapeutic effect of a sodium pentaborate-based topical formulation compared to control on the treatment of diabetic foot ulcers. METHODS: A prospective, double-blind, randomized controlled trial was conducted to apply randomly the topical sodium pentaborate 3% gel or topical conventional remedy (control) by patients diagnosed with diabetic foot ulcers. The 171 eligible participants aged 18-75 years received the allocated medicines twice a day for a month with an allocation ratio of 3:1. Twenty-five days and two months after the end of the trial, participants were reinvestigated for their ulcer condition and any recurrence. Wagner's classification of diabetic foot ulcers was applied to this purpose (0-5). RESULTS: 161 participants (57 females, 104 males; mean age: 59.37) completed this study. After the intervention, most participants in the intervention group had a lower ulcer grade than the control group (adjusted mean difference (95% CI): - 0.91 (-1.1 to -0.73); p < 0.001). Moreover, most participants in the intervention group (n = 109 (90.8%)) were treated at a higher rate than the control group (n = 5 (12.2%)) after intervention (adjusted odds ratio (95% CI): 0.008 (0.002-0.029); p < 0.001). There was no case of recurrence in the intervention group while its rate was (n = 2 (40%)) in the control group (p < 0.001). CONCLUSION: The present study suggests that topical sodium pentaborate gel may help treat and decrease the grade of diabetic foot ulcers and prevent the recurrence of diabetic foot ulcers.

Efficient neutron capture therapy of glioblastoma with pteroyl-closo-dodecaborate-conjugated 4-(p-iodophenyl)butyric acid (PBC-IP).

Boron neutron capture therapy (BNCT) has been applied for clinical trials on glioblastoma patients since 1950s, however, the low survival rate under the treatments has hampered the widespread use of BNCT. In this study, we developed a novel boron agent, PBC-IP, which consists of three functional groups: FRα-targeting, 10B resource (twelve 10B atoms in the molecule), and albumin-binding moieties. PBC-IP was selectively taken up by glioma cell lines such as C6, F98, and U87MG cells and accumulated 10- to 20-fold higher than L-4­boronophenylalanine (BPA). PBC-IP administrated intravenously to the human glioblastoma (U87MG) xenograft model showed higher boron accumulation in tumors (29.8 µg [10B]/g at 6 h) than BPA (9.6 µg [10B]/g at 3 h) at a 25 mg [10B]/kg dose, effectively suppressing tumor growth after thermal neutron irradiation. PBC-IP administrated via convection-enhanced delivery (CED) accumulated in the F98 glioma orthotopic rat model, achieving 26.5 µg [10B]/g in tumors with tumor/normal (T/N) brain and tumor/blood (T/B) boron ratios of 37.8 and 94.6, respectively, 3 h after CED. Survival at 180 days after BNCT was 50% in the PBC-IP group and 70% in the combined BPA and PBC-IP groups, with no residual brain tumors.

Boron uptake of boronophenylalanine and the effect of boron neutron capture therapy in cervical cancer cells.

There are few studies about boron neutron capture therapy (BNCT) for cervical cancer. The present study evaluated the biodistribution of boronophenylalanine (BPA) and the effect of BNCT on cervical cancer cell lines. BPA exposure and neutron irradiation of cervical cancer cell lines resulted in decreased survival fraction compared to irradiation only. In vivo cervical cancer tumor boron concentration was highest at 2.5 h after BPA intraperitoneal administration, and higher than in the other organs. BNCT may be effective against cervical carcinoma.

[Basic Organic and Inorganic Chemistry of Boron Clusters and Its Application to Drug Discovery].

In the past, drug discovery using low-molecular-weight compounds was dominated by structural design based on combinations of non-metallic elements such as carbon, nitrogen, oxygen, and halogens. Recent drug discovery efforts have shown extraordinary progress, an example of which is the adoption of non-universal elements. The approval of boron neutron capture therapy (BNCT) using a neutron accelerator in Japan ahead of other countries is still fresh in our memory. Other small-molecule drugs containing boron atoms have also been developed, and boron is becoming widely recognized as a constituent element for drug discovery. It is known that borane (BH3) is unstable because of its electron-deficient bonds; nevertheless, its stability has been improved by the formation of clusters through multimerization. Carborane (C2B10H12), one of the borane clusters, has an icosahedral structure with two carbon atoms and ten boron atoms and exhibits properties that vastly differ from conventional boron compounds. In this symposium review, we will introduce the basic chemistry of carboranes and their application to drug discovery. Boron is an essential element in plant cell wall formation and has extremely low toxicity to humans. I hope that this symposium review will be an opportunity for us to free ourselves from existing prejudices and constraints in drug discovery, and that new modalities that skillfully utilize the characteristics of boron and boron clusters will be developed one after another.

Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment.

Boron neutron capture therapy (BNCT) is one of the most promising treatments among neutron capture therapies due to its long-term clinical application and unequivocally obtained success during clinical trials. Boron drug and neutron play an equivalent crucial role in BNCT. Nevertheless, current clinically used l-boronophenylalanine (BPA) and sodium borocaptate (BSH) suffer from large uptake dose and low blood to tumor selectivity, and that initiated overwhelm screening of next generation of BNCT agents. Various boron agents, such as small molecules and macro/nano-vehicles, have been explored with better success. In this featured article, different types of agents are rationally analyzed and compared, and the feasible targets are shared to present a perspective view for the future of BNCT in cancer treatment. This review aims at summarizing the current knowledge of a variety of boron compounds, reported recently, for the application of BCNT.

Localized nuclear reaction breaks boron drug capsules loaded with immune adjuvants for cancer immunotherapy.

Boron neutron capture therapy (BNCT) was clinically approved in 2020 and exhibits remarkable tumour rejection in preclinical and clinical studies. It is binary radiotherapy that may selectively deposit two deadly high-energy particles (4He and 7Li) within a cancer cell. As a radiotherapy induced by localized nuclear reaction, few studies have reported its abscopal anti-tumour effect, which has limited its further clinical applications. Here, we engineer a neutron-activated boron capsule that synergizes BNCT and controlled immune adjuvants release to provoke a potent anti-tumour immune response. This study demonstrates that boron neutron capture nuclear reaction forms considerable defects in boron capsule that augments the drug release. The following single-cell sequencing unveils the fact and mechanism that BNCT heats anti-tumour immunity. In female mice tumour models, BNCT and the controlled drug release triggered by localized nuclear reaction causes nearly complete regression of both primary and distant tumour grafts.

Preparation and tumor-targeting evaluation of BS-CyP albumin nanoparticles modified with hyaluronic acid based on boron neutron capture therapy.

Radiation therapy has been widely used in the clinical treatment of tumors. Due to the low radiation absorption of tumors, a high dose of ionizing radiation is often required during radiotherapy, which causes serious damage to normal tissues near tumors. Boron neutron capture therapy (BNCT) is more targeted than conventional radiotherapy. To improve the therapeutic effect of cancer, albumin was selected as the drug carrier to wrap the fluorescent tracer boron drug BS-CyP and prepare the nanoparticles. Then, we developed a novel tumor-targeting nano-boron drug by using hyaluronic acid to modify the nanoparticles. We found that BS-CyP albumin nanoparticles modified with hyaluronic acid effectively delayed drug release and enhanced the aggregation, in tumors, showing good safety with no obvious toxicity to cells and mice. This study confirmed the advantages of boron drugs modified with hyaluronic acid targeting tumors and may provide a reference for BNCT.

A Comparison of Boron Supplement and Tamsulosin as Medical Expulsive Therapy for Urinary Stones After Extracorporeal Shock Wave Lithotripsy: a Randomized Controlled Clinical Trial.

Treatment with alpha-blockers has been used in many studies to facilitate stone clearance after extra-corporeal shock wave lithotripsy (ESWL), based on mediating ureteral wall relaxation. Ureteral wall edema is another barrier against the stone passage. We aimed to compare the effectiveness of boron supplement (due to its anti-inflammatory effect) and tamsulosin in the passage of stone fragments after ESWL. Eligible patients after ESWL were randomly assigned to two groups and were treated with boron supplement (10 mg/BD) or tamsulosin (0.4 mg per night) for 2 weeks. The primary outcome was the stone expulsion rate according to the remained fragmented stone burden. The secondary outcomes were the time of stone clearance, pain intensity, drug side effects, and the need for auxiliary procedures. In this randomized control trial, 200 eligible patients were treated with boron supplement or tamsulosin. Finally, 89 and 81 patients in the two groups completed the study, respectively. The expulsion rate was 46.6% in the boron and 38.7% in the tamsulosin group, which there was no statistically significant difference between the two groups (p = 0.003), as well as the time of stone clearance (7.47 ± 22.4 vs 6.52 ± 18.45, days, p = 0.648, respectively), after 2-week follow-up. Moreover, pain intensity was the same in both groups. No Significant side effects were reported in the two groups. Boron supplement could be effective as adjuvant medical expulsive therapy after ESWL with no significant side effects in short-term follow-up. Iranian Clinical Trial Registration number and date of registration: IRCT20191026045244N3, 07/29/2020.

Boron-Containing Compounds for Prevention, Diagnosis, and Treatment of Human Metabolic Disorders.

The application of natural and synthetic boron-containing compounds (BCC) in biomedical field is expanding. BCC have effects in the metabolism of living organisms. Some boron-enriched supplements are marketed as they exert effects in the bone and skeletal muscle; but also, BCC are being reported as acting on the enzymes and transporters of membrane suggesting they could modify the carbohydrate metabolism linked to some pathologies of high global burden, as an example is diabetes mellitus. Also, some recent findings are showing effects of BCC on lipid metabolism. In this review, information regarding the effects and interaction of these compounds was compiled, as well as the potential application for treating human metabolic disorders is suggested.

New Boron Delivery Agents.

This proceeding article compiles current research on the development of boron delivery drugs for boron neutron capture therapy that was presented and discussed at the National Cancer Institute (NCI) Workshop on Neutron Capture Therapy that took place on April 20-22, 2022. The most used boron sources are icosahedral boron clusters attached to peptides, proteins (such as albumin), porphyrin derivatives, dendrimers, polymers, and nanoparticles, or encapsulated into liposomes. These boron clusters and/or carriers can be labeled with contrast agents allowing for the use of imaging techniques, such as PET, SPECT, and fluorescence, that enable quantification of tumor-localized boron and their use as theranostic agents.

The dual role of boron in vitro neurotoxication of glioblastoma cells via SEMA3F/NRP2 and ferroptosis signaling pathways.

Glioblastoma multiform (GBM) is a malignant tumor cancer that originates from the star-shaped glial support tissues, namely astrocytes, and it is associated with a poor prognosis in the brain. The GBM has no cure, and chemotherapy, radiation therapy, and immunotherapy are all ineffective. A certain dose of Boric acid (BA) has many biochemical effects, conspicuously over antioxidant/oxidant rates. This article sought to investigate the modifies of various doses of BA on the glioblastoma concerning cytotoxicity, ferroptosis, apoptosis, and semaphorin-neuropilin signaling pathway. The Cytotoxic activity and cell viability of BA (0.39-25 mM) in C6 cells were tested at 24, 48, and 72 h using 3-(4,5-dimethylthiazol, 2-yl)-2,5-diphenyl tetrazolium bromide (MTT). The IC50 concentration of BA at 1.56 mM was found and cell lysate used for biochemical analysis. Glutathione peroxidase 4 (GPx4) and ACLS4 levels of ferroptosis, levels of total antioxidant (TAS) and oxidant (TAS) parameters, malondialdehyde (MDA), apoptotic proteins as caspase 3 (CASP3) and caspase 7 (CASP7) were measured. The ferroptosis, semaphoring-neuropilin, apoptotic pathway markers and cell counts were analyzed with flow cytometry, Q-PCR, Western and Elisa technique in the C6 cell lysate. BA triggered ferroptosis in the C6 cells dose-dependently, affecting the semaphorin pathway, so reducing proliferation with apoptotic compared with untreated cell as control group (p < .05). This study revealed that BA, defined as trace element and natural compound, incubated ferroptosis, total oxidant molecules, and caspase protein in a dose-dependently by disrupting SEMA3F in tumor cells.

Enhancement of ferroptosis by boric acid and its potential use as chemosensitizer in anticancer chemotherapy.

Ferroptosis is a form of regulated cell death (RCD) characterized by intracellular iron ion accumulation and reactive oxygen species (ROS)-induced lipid peroxidation. Ferroptosis in cancer and ferroptosis-related anticancer drugs have recently gained interest in the field of cancer treatment. Boron is an essential trace element playing an important role in several biological processes. Recent studies have described contrasting effects of boric acid (BA) in cancer cells, ranging from protective/mitogenic to damaging/antiproliferative. Interestingly, boron has been shown to interfere with critical factors involved in ferroptosis-intracellular glutathione and lipid peroxidation in the first place. Thus, the present study was aimed to verify the ability of boron to modulate the ferroptotic process in HepG2 cells, a model of hepatocellular carcinoma. Our results indicate that-when used at high, pharmacological concentrations-BA can increase intracellular ROS, glutathione, and TBARS levels, and enhance ferroptosis induced by RSL3 and erastin. Also, high BA concentrations can directly induce ferroptosis, and such BA-induced ferroptosis can add to the cytotoxic effects of anticancer drugs sorafenib, doxorubicin and cisplatin. These observations suggest that BA could be exploited as a chemo-sensitizer agent in order to overcome cancer drug resistance in selected conditions. However, the possibility of reaching suitably high concentrations of BA in the tumor microenvironment will need to be further investigated.

Investigation of cytotoxic and apoptotic effects of disodium pentaborate decahydrate on ovarian cancer cells and assessment of gene profiling.

After revealing the anti-cancer properties of boron, which is included in the category of essential elements for human health by the World Health Organization, the therapeutic potential of boron compounds has been begun to be evaluated, and its molecular effect mechanisms have still been among the research subjects. In ovarian cancer, mutations or amplifications frequently occur in the PI3K/Akt/mTOR pathway components, and dysregulation of this pathway is shown among the causes of treatment failure. In the present study, it was aimed to investigate the anti-cancer properties of boron-containing DPD in SKOV3 cells, which is an epithelial ovarian cancer model, through PI3K/AKT/mTOR pathway. The cytotoxic activity of DPD in SKOV3 cells was evaluated by WST-1 test, apoptotic effect by Annexin V and JC-1 test. The gene expressions associated with PI3K/AKT/mTOR pathway were determined by real-time qRT-PCR. In SKOV3 cells, the IC50 value of DPD was found to be 6.7 mM, 5.6 mM, and 5.2 mM at 24th, 48th and 72nd hour, respectively. Compared with the untreated control group, DPD treatment was found to induce apoptosis 2.6-fold and increase mitochondrial membrane depolarization 4.5-fold. DPD treatment was found to downregulate PIK3CA, PIK3CG, AKT2, IGF1, IRS1, MAPK3, HIF-1, VEGFC, CAB39, CAB39L, STRADB, PRKAB2, PRKAG3, TELO2, RICTOR, MLST8, and EIF4B genes and upregulate TP53, GSK3B, FKBP8, TSC2, ULK1, and ULK2 genes. These results draw attention to the therapeutic potential of DPD, which is frequently exposed in daily life, in epithelial ovarian cancer and show that it can be a candidate compound in combination with chemotherapeutics.