Boron Neutron Capture Therapy Applications Research Articles

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.

Boron Neutron Capture Therapy Enhanced by Boronate Ester Polymer Micelles: Synthesis, Stability, and Tumor Inhibition Studies.

Boron neutron capture therapy (BNCT) targets invasive, radioresistant cancers but requires a selective and high B-10 loading boron drug. This manuscript investigates boron-rich poly(ethylene glycol)-block-(poly(4-vinylphenyl boronate ester)) polymer micelles synthesized via atom transfer radical polymerization for their potential application in BNCT. Transmission electron microscopy (TEM) revealed spherical micelles with a uniform size of 43 ± 10 nm, ideal for drug delivery. Additionally, probe sonication proved effective in maintaining the micelles' size and morphology postlyophilization and reconstitution. In vitro studies with B16-F10 melanoma cells demonstrated a 38-fold increase in boron accumulation compared to the borophenylalanine drug for BNCT. In vivo studies in a B16-F10 tumor-bearing mouse model confirmed enhanced tumor selectivity and accumulation, with a tumor-to-blood (T/B) ratio of 2.5, surpassing BPA's T/B ratio of 1.8. As a result, mice treated with these micelles experienced a significant delay in tumor growth, highlighting their potential for BNCT and warranting further research.

Synthesis and Characterization of B4C-Based Multifunctional Nanoparticles for Boron Neutron Capture Therapy Applications

Nanoparticles composed of inorganic boron-containing compounds represent a promising candidate as 10B carriers for BNCT. This study focuses on the synthesis, characterization, and assessment of the biological activity of composite nanomaterials based on boron carbide (B4C). Boron carbide is a compelling alternative to borated molecules due to its high volumetric B content, prolonged retention in biological systems, and low toxicity. These attributes lead to a substantial accumulation of B in tissues, eliminating the need for isotopically enriched compounds. In our approach, B4C nanoparticles were included in composite nanostructures with ultrasmall superparamagnetic nanoparticles (SPIONs), coated with poly (acrylic acid), and further functionalized with the fluorophore DiI. The successful internalization of these nanoparticles in HeLa cells was confirmed, and a significant uptake of 10B was observed. Micro-distribution studies were conducted using intracellular neutron autoradiography, providing valuable insights into the spatial distribution of the nanoparticles within cells. These findings strongly indicate that the developed nanomaterials hold significant promise as effective carriers for 10B in BNCT, showcasing their potential for advancing cancer treatment methodologies.

Advancements in the Synthesis and Biological Properties of Carboranes and High‑Boron Related Compounds: A Comprehensive Exploration with Emphasis on BNCT Applications

Since Locher proposed the concept of boron neutron capture therapy (BNCT) in 1936, it has become a great challenge in the field of medicinal chemistry. The great dare has been to obtain boron-containing compounds that selectively accumulate in the organ to be irradiated. Polyhedral boron clusters (PBC) have been considered attractive moieties for the development of BNCT-agents due to their large contribution of boron per molecule. Various issues arose in the first efforts to develop PBC during the 1940-1950s that prevented their application in BNCT clinical trials, such as a lack of selectivity and low boron tumor-accumulation. Currently, the most studied PBC in BNCT are the icosahedral dicarba-closo-dodecaboranes (C2B10H12) commonly referred to carboranes and, to a lesser extent, their mono-anionic derivatives resulting from the loss of a B-vertex, commonly known as nido-carborane, and their metal complexes, known as metallacarboranes. This review will cover the medicinal chemistry of PBC for BNCT.

Boron Neutron Capture Therapy Application and Prospects

Boron Neutron Capture Therapy Application and Prospects

Peptide Conjugated Boron Neutron Capture Therapy for Enhanced Tumor Targeting.

A cutting-edge non-invasive cancer treatment method called boron neutron capture therapy (BNCT) allows for the removal of cancerous tumor cells with the least possible damage to healthy tissue. It involves the exposure of cancer cells with low-energy thermal neutrons, boron-10 (10B) cellular uptake causes cancer cell death by producing alpha particles and recoiling lithium-7 (7 Li) nuclei. Despite positive outcomes from clinical trials conducted all around the world, these substances have relatively limited tumor selectivity or low boron content per molecule. The development of new boron delivery agents with more selectivity and enhanced boron loading would advance this technique and promote its use in clinics as a primary cancer treatment. As peptide-binding cell surface receptors are typically overexpressed on cancer cells, they can be seen as interesting targets for targeted tumor therapy. The attachment of meta-carboranes to peptide conjugates that target tumor cells specifically by their overexpressed receptors may be a method to get around these problems. A state-of-the-art overview of current developments in the application of BNCT for cancer targeted therapy via peptide conjugation is the goal of this review.

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.

Design of beam line for BNCT applications in HEC-1 channel of IRT-T research reactor

The feasibility of using the HEC-1 beam port of the IRT-T research reactor to generate an epithermal neutron beam for Boron Neutron Capture Therapy (BNCT) was investigated using MCNPX2.6 Monte Carlo simulation. The reactor was first simulated to design and optimize a Beam Shaping Assembly (BSA) that meets the neutron beam criteria recommended by the International Atomic Energy Agency (IAEA). The suggested BSA configuration consisted of a cylindrical geometry with 25 cm of MgF2 and 15 cm of Fluental® as a moderator, 15 cm of Pb as a reflector, two 5 cm Bi slabs as gamma-ray shields, and 4 mm of 6Li and 5 mm of borated polyethylene sheets as thermal neutron filters. The results showed that the epithermal neutron flux at the BSA exit was 2.3×109 n/cm2.s, and in-phantom dose analysis indicated that the designed beam could be used for the treatment of deep brain tumors within an allowable treatment time of 50 min.

Development of an automatic optimization program for the weight of multi-field irradiation in BNCT based on a genetic algorithm

ABSTRACT Boron Neutron Capture Therapy (BNCT) is a promising radiotherapy technique for cancer treatment. Optimizing dose distribution in tumors is a significant challenge for BNCT, especially for tumors that are deep-seated. The method of optimizing dose distribution through multi-field irradiation holds great potential for clinical applications in BNCT. This study presents an optimization program that couples genetic algorithm and Monte Carlo simulation, which can automatically optimize irradiation field weights for multi-field irradiation, ensuring optimal dose distribution for cancer patients. Using this program, a glioblastoma case was used to analyze the optimization results for different numbers of irradiation fields. The results demonstrate that the program possesses an efficient and accurate automatic optimization feature for multi-field irradiation weights. The minimum dose, mean dose, and D80% of tumor dose improve with the increase in irradiation fields, while the homogeneity index (HI) of tumor dose decreases, without exceeding dose constraints for organs at risk. The developed optimization program provides a method for determining irradiation field weights in BNCT treatment planning systems, which has the potential to improve treatment outcomes.

Boron neutron capture therapy anti-tumor effect of nanostructured boron carbon nitride: A new potential candidate

Boron Neutron Capture Therapy (BNCT) is a targeted radiotherapy modality in which 10B enriched compounds are delivered for local treatment of the cancer cells. In this work, boron carbon nitride (BCN) has been explored as a potential boron compound for BNCT. BCN compound with high solubility has been synthesized by simple solvothermal method. Structural analysis show synthesis of hexagonal BCN with presence of defect states. Morphological analysis show formation of layered structure with highly porous network. The optical properties have also been studied and calculated band gap of material is ∼3.85 eV. Cytotoxicity analysis show that synthesized material is relatively less toxic and can be explored for BNCT applications. The anti-tumor effect on HeLa and U-87MG cell lines show potential of BCN in comparison to clinically studied L-BPA compound.

In-air experimental achievement of high-voltage DC power supply to be installed in a tandem electrostatic accelerator system for boron neutron capture therapy application.

The boron neutron capture therapy (BNCT) system developed by the Korea Institute of Radiological and Medical Sciences is a compact neutron source that can be installed at medical institutes. The target energy was accelerated to a maximum of 2.4 MeV-20 mA by introducing a gas stripping device that converts negative hydrogen ions into positive ions. By using the tandem-type accelerator in this way, a high-voltage DC power supply was designed with 1.2 MV-45 mA as the maximum capability. The design was improved to reduce the number of stages of a Cockcroft-Walton voltage multiplier. Hence, the ripple risk of the DC flat top resulting from unwanted stray capacitance was lowered. The overall height and volume of the Cockcroft-Walton voltage multiplier were reduced to less than half those of the existing design method, making miniaturization possible. After such advanced design and manufacturing, performance tests were performed at 750 kV-45 mA under 23 stages of the Cockcroft-Walton voltage multiplier, which is the highest level that can perform at its maximum under in-air conditions. It demonstrated stable performance under in-air conditions without breakdown for 2h, even at 620 kV-35 mA. To reach the final target of 1.2 MV-45 mA, the groundwork is laid for achieving experimental performance while satisfying the optimal requirements in SF6 gas.

A large area, high counting rate micromegas-based neutron detector for BNCT

Beam monitoring and evaluation are very important to boron neutron capture therapy (BNCT), and a variety of detectors have been developed for these applications. However, most of the detectors used in BNCT only have a small detection area, leading to the inconvenience of the full-scale 2-D measurement of the beam. Based on micromegas technology, we designed a neutron detector with large detection area and high counting rate. This detector has a detection area of 288 mm × 288 mm and can measure thermal, epithermal, and fast neutrons with different detector settings. The BNCT experiments demonstrated that this detector has a very good 2-D imaging performance for the thermal, epithermal, fast neutron and gamma components, a highest counting rate of 94 kHz/channel, and a good linearity response to the beam power. Additionally, the flux fraction of each component can be calculated based on the measurement results. The Am-Be neutron source experiment indicates that this detector has a spatial resolution of approximately 1.4 mm, meeting the requirements of applications in BNCT. It is evident that this micromegas-based neutron detector with a large area and high counting rate capability has great development prospects in BNCT beam monitoring and evaluation applications.

Evaluating the biological effectiveness of boron neutron capture therapy by using microfluidics-based pancreatic tumor spheroids.

Background: The recent success of boron neutron capture therapy (BNCT) for cancer treatment has attracted considerable attention. Because irradiated neutrons penetrate deep into solid tumor tissue, BNCT efficacy is strongly influenced by cell pathophysiology in tumors. The tumor microenvironment critically influences tumor pathophysiology, but its effects on BNCT remain unexplored. Methods: We used a pancreatic tumor as a model to develop a high-throughput 3D tumor spheroid platform for evaluating BNCT efficacy under different microenvironment conditions. We expanded our system to serve as a transwell-like device in order to investigate the influence of stromal fibroblasts in the tumor microenvironment. Results: With the use of the proposed microfluidic chip and a laboratory pipette, more than 40 spheroids with controllable diameters (standard deviation <10%) could be cultured on a chip for more than 10 days. The response to BNCT from each spheroid can be monitored in real time. By using pancreatic tumor spheroids of two different diameters, we found that large spheroids, characterized by more hypoxic microenvironments, exhibited lower BNCT susceptibility. The cells in the hypoxic region expressed the HIF1-α signal, which is crucial in many therapeutic resistance signal pathways. In addition, the heterogeneous presence of stemness markers (Oct-4, Sox-2, and CD 44) implied that the underlying BNCT resistance mechanism was sophisticated. In the presence of fibroblasts, we found an association between β-catenin nuclear translocation and BNCT resistance; membrane contacts from fibroblasts were found to be indispensable for translocation activation. Conclusions: In summary, by means of easily accessible microfluidic engineering, we developed tumor spheroids to recapture the pathophysiological characteristics of pancreatic tumors. Our data suggest that hypoxia and fibrosis can reduce BNCT efficacy in pancreatic cancer treatment. Considering the growing requirement for drug screening in personalized medicine, our findings and the developed method are expected to improve the fundamental understanding of BNCT and facilitate broad applications of BNCT in clinical settings.

A transdermal drug delivery system based on dissolving microneedles for boron neutron capture therapy of melanoma.

Boron neutron capture therapy (BNCT) is a promising therapy for malignant tumors that requires selective and high concentrations of 10B accumulation in tumor cells. Despite ongoing developments in novel boron agents and delivery carriers, the progress and clinical application of BNCT is still restricted by the low 10B accumulation and tumor-to-normal tissue (T/N) ratio. Herein, a dissolving microneedle-based transdermal drug delivery system was specifically designed for BNCT in a mouse model of melanoma. By incorporating fructose-BPA (F-BPA) into PVA microneedle tips, this system successfully delivered sufficient F-BPA into the melanoma site after the application of only two patches. Notably, the T/N ratio achieved through the treatment combining PVA/F-BPA MNs with BNCT (PVA/F-BPA MNs-BNCT) surpassed 93.16, signifying a great improvement. Furthermore, this treatment approach effectively inhibited tumor growth and significantly enhanced the survival rate of the mice. In brief, our study introduces a novel, simple, and efficient administration strategy for BNCT, opening new possibilities for the design of nanomedicine for BNCT.

Carborane-Containing Folic Acid bis-Amides: Synthesis and In Vitro Evaluation of Novel Promising Agents for Boron Delivery to Tumour Cells.

The design of highly selective low-toxic, low-molecular weight agents for boron delivery to tumour cells is of decisive importance for the development of boron neutron capture therapy (BNCT), a modern efficient combined method for cancer treatment. In this work, we developed a simple method for the preparation of new closo- and nido-carborane-containing folic acid bis-amides containing 18-20 boron atoms per molecule. Folic acid derivatives containing nido-carborane residues were characterised by high water solubility, low cytotoxicity, and demonstrated a good ability to deliver boron to tumour cells in in vitro experiments (up to 7.0 µg B/106 cells in the case of U87 MG human glioblastoma cells). The results obtained demonstrate the high potential of folic acid-nido-carborane conjugates as boron delivery agents to tumour cells for application in BNCT.

Design, Fabrication and Characterization of Biodegradable Composites Containing Closo-Borates as Potential Materials for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) has been recognized as a very promising approach for cancer treatment. In the case of osteosarcoma, boron-containing scaffolds can be a powerful tool to combine boron delivery to the tumor cells and the repair of postoperative bone defects. Here we describe the fabrication and characterization of novel biodegradable polymer composites as films and 3D-printed matrices based on aliphatic polyesters containing closo-borates (CB) for BNCT. Different approaches to the fabrication of composites have been applied, and the mechanical properties of these composites, kinetics of their degradation, and the release of closo-borate have been studied. The most complex scaffold was a 3D-printed poly(ε-caprolactone) matrix filled with CB-containing alginate/gelatin hydrogel to enhance biocompatibility. The results obtained allowed us to confirm the high potential of the developed composite materials for application in BNCT and bone tissue regeneration.

Design and Development of Gold-Loaded and Boron-Attached Multicore Manganese Ferrite Nanoparticles as a Potential Agent in Biomedical Applications.

Early diagnosis and effective treatment of cancer are significant issues that should be focused on since it is one of the most deadly diseases. Multifunctional nanomaterials can offer new cancer diagnoses and treatment possibilities. These nanomaterials with diverse functions, including targeting, imaging, and therapy, are being studied extensively in a way that minimize overcoming the limitations associated with traditional cancer diagnosis and treatment. Therefore, the goal of this study is to prepare multifunctional nanocomposites possessing the potential to be used simultaneously in imaging such as magnetic resonance imaging (MRI) and dual cancer therapy such as photothermal therapy (PTT) and boron neutron capture therapy (BNCT). In this context, multi-core MnFe2O4 nanoparticles, which can be used as a potential MRI contrast agent and target the desired region in the body via a magnetic field, were successfully synthesized via the solvothermal method. Then, multi-core nanoparticles were coated with polydopamine (PDA) to reduce gold nanoparticles, bind boron on the surface, and ensure the biocompatibility of all materials. Finally, gold nanoparticles were reduced on the surface of PDA-coated MnFe2O4, and boric acid was attached to the hybrid materials for also possessing the ability to be used as a potential agent in PTT and BNCT applications in addition to being an MRI agent. According to the cell viability assay, treatment of the glioblastoma cell line (T98G) with MnFe2O4@PDA-Au-BA for 24 and 48 h did not cause any significant cell death, indicating good biocompatibility. All analysis results showed that the developed MnFe2O4@PDA-Au-BA multifunctional material could be a helpful candidate for biomedical applications such as MRI, PTT, and BNCT.

Boron concentration prediction from Compton camera image for boron neutron capture therapy based on generative adversarial network

Prompt gamma monitoring for the prediction of boron concentration is valuable for the dose calculation of boron neutron capture therapy (BNCT). This work proposes to use generative adversarial network (GAN) to predict the boron distribution based on Compton camera (CC) imaging quickly and provide a scientific basis for its application in BNCT. The BNCT and Compton imaging process was simulated, then the image reconstructed from the simulation and the contour of skin from CT are used as input, and the distribution of boron concentration from PET data is set as the output to train the network. The structural similarity, peak signal-to-noise ratio, and root mean square error of the images generated by the trained network are improved significantly, and the ratio of the boron concentration between the tumor area and the normal tissue is improved from 1.55 to 3.85, which is much closer to the true value of 3.52. The trained network can optimize the original image within 0.83 s, which is much faster than iterative optimization. The proposed method could help to ease the current online monitoring problem of boron concentration on a computational level, thereby promoting the clinical development of BNCT technology.

Therapeutic nucleus-access BNCT drug combined CD47-targeting gene editing in glioblastoma

Glioblastoma is the most common brain primary malignant tumor with the highest mortality. Boron neutron capture therapy (BNCT) can efficiently kill cancer cells on the cellular scale, with high accuracy, short course and low side-effects, which is regarded as the most promising therapy for malignant brain tumors like glioma. As the keypoint of BNCT, all boron delivery agents currently in clinical use are beset by insufficient tumor uptake, especially in the tumor nucleus, which limits the clinical application of BNCT. In this study, nuclear targeting of boron is achieved by DOX-CB, consisting of doxorubicin (DOX) and carborane (CB) utilizing the nuclear translocation property of DOX. The nucleus of GL261 cells takes up almost three times the concentration of boron required for BNCT. To further kill glioma and inhibit recurrence, a new multifunctional nanoliposome delivery system DOX-CB@lipo-pDNA-iRGD is constructed. It combines DOX-CB with immunotherapy strategy of blocking macrophage immune checkpoint pathway CD47-SIRPα by CRISPR-Cas9 system, coupling BNCT with immunotherapy simultaneously. Compared with clinical drug Borocaptate Sodium (BSH), DOX-CB@lipo-pDNA-iRGD significantly enhances the survival rate of tumor-bearing mice, reduces tumor stemness, and improves the prognosis. The excellent curative effect of this nanoliposome delivery system provides an insight into the combined treatment of BNCT.Graphical

Multimodal evaluation of 19F-BPA internalization in pancreatic cancer cells for boron capture and proton therapy potential applications.

One of the obstacles to the application of Boron Neutron Capture Therapy (BNCT) and Proton Boron Fusion Therapy (PBFT) concerns the measurement of borated carriers' biodistribution. The objective of the present study was to evaluate the in vitro internalization of the 19F-labelled p-boronophenylalanine (19F-BPA) in the human cancer pancreatic cell line (PANC-1) for the potential application of BNCT and PBFT in pancreatic cancer. The 19F-BPA carrier has the advantage that its bio-distribution may be monitored in vivo using 19F-Nuclear Magnetic Resonance (19F NMR). The 19F-BPA internalization in PANC-1 cells was evaluated using three independent techniques on cellular samples left in contact with growing medium enriched with 13.6mM 19F-BPA corresponding to a 11B concentration of 120ppm: neutron autoradiography, which quantifies boron; liquid chromatography hyphenated to tandem mass spectrometry and UV-Diode Array Detection (UV-DAD), which quantifies 19F-BPA molecule; and 19F NMR spectroscopy, which detects fluorine nuclei. Our studies suggested that 19F-BPA is internalized by PANC-1 cells. The three methods provided consistent results of about 50% internalization fraction at 120ppm of 11B. Small variations (less than 15%) in internalization fraction are mainly dependent on the proliferation state of the cells. The ability of 19F NMR spectroscopy to study 19F-BPA internalization was validated by well-established independent techniques. The multimodal approach we used suggests 19F-BPA as a promising BNCT/PBFT carrier for the treatment of pancreatic cancer. Since the quantification is performed at doses useful for BNCT/PBFT, 19F NMR can be envisaged to monitor 19F-BPA bio-distribution during the therapy.