Neutron Capture Therapy Agents Research Articles

Nucleoside Scaffolds and Carborane Clusters for Boron Neutron Capture Therapy: Developments and Future Perspective.

Nucleosides containing carboranes are one of the most important boron delivery agents for boron neutron capture therapy, BNCT, which are good substrates of hTK1. The development of several nucleosides containing carboranes at early stages led to the discovery of the first generation of 3CTAs by incorporating a hydrocarbon spacer between the thymidine scaffold and carborane cluster and attaching dihydroxylpropyl group on the second carbon (C2) atom of the carborane cluster (e.g., N5 and N5-2OH). Phosphorylation rate, tumor cellular uptake, and retention have been evaluated in parallel to change the length of the tether arm of spacers in these compounds. Many attempts were reported and discussed to overcome the disadvantage of the first generation of 3CTAs by a) incorporating modified spacers between thymidine and carborane clusters, such as ethyleneoxide, polyhydroxyl, triazole, and tetrazole units, b) attaching hydrophilic groups at C2 of the carborane cluster, c) transforming lipophilic closo-carboranes to hydrophilic nidocarborane. The previous modifications represented the second generation of 3CTAs to improve the hydrogen bond formation with the hTK1 active site. Moreover, amino acid prodrugs were developed to enhance biological and physicochemical properties. The structure-activity relationship (SAR) of carboranyl thymidine analogues led to the roadmap for the development of the 3rd generation of the 3CTAs for BNCT.

A Bis-Boron Amino Acid for Positron Emission Tomography and Boron Neutron Capture Therapy.

Trifluoroborate boronophenylalanine (BBPA) is a boron amino acid analog of 4‑boronophenylalanine (BPA) but with a trifluoroborate group (-BF3-) instead of a carboxyl group (-COOH). Clinical studies have shown that 18F-labeled BBPA ([18F]BBPA) can produce high-contrast tumor images in positron emission tomography (PET). Beyond PET imaging, BBPA is a theranostic agent for boron neutron capture therapy (BNCT). Because BBPA possesses an identical chemical structure to BNCT and PET, it can potentially predict the boron concentration for BNCT using [18F]BBPA-PET. The synthesis of BBPA was achieved by selectively fluorinating the α-aminoborate compound, taking advantage of the varying rates of solvolysis of the B-F bond. The study showcased the high-contrast [18F]BBPA-PET imaging in various tumor models, highlighting its broad applicability for both [18F]BBPA-PET and BBPA-BNCT. [18F]BBPA-PET tumor uptake remains consistent across various doses, including those used in BNCT. This enables accurate estimation of the boron concentration in tumors using [18F]BBPA-PET. With its dual boron structure, BBPA increases boron concentration in tumor cells and tumor tissues compared to BPA. Thus, less boron carrier is needed. This study introduces a new theranostic boron carrier that enhances boron accumulation in tumors, predicts boron concentration, and enhances the accuracy and effectiveness of BNCT.

A Bis‐Boron Amino Acid for Positron Emission Tomography and Boron Neutron Capture Therapy

Trifluoroborate boronophenylalanine (BBPA) is a boron amino acid analog of 4‑boronophenylalanine (BPA) but with a trifluoroborate group (‐BF3‐) instead of a carboxyl group (‐COOH). Clinical studies have shown that 18F‐labeled BBPA ([18F]BBPA) can produce high‐contrast tumor images in positron emission tomography (PET). Beyond PET imaging, BBPA is a theranostic agent for boron neutron capture therapy (BNCT). Because BBPA possesses an identical chemical structure to BNCT and PET, it can potentially predict the boron concentration for BNCT using [18F]BBPA‐PET. The synthesis of BBPA was achieved by selectively fluorinating the α‐aminoborate compound, taking advantage of the varying rates of solvolysis of the B‐F bond. The study showcased the high‐contrast [18F]BBPA‐PET imaging in various tumor models, highlighting its broad applicability for both [18F]BBPA‐PET and BBPA‐BNCT. [18F]BBPA‐PET tumor uptake remains consistent across various doses, including those used in BNCT. This enables accurate estimation of the boron concentration in tumors using [18F]BBPA‐PET. With its dual boron structure, BBPA increases boron concentration in tumor cells and tumor tissues compared to BPA. Thus, less boron carrier is needed. This study introduces a new theranostic boron carrier that enhances boron accumulation in tumors, predicts boron concentration, and enhances the accuracy and effectiveness of BNCT.

Dative Bonding Activation Enables Precise Functionalization of the Remote B-H Bond of nido-Carborane Clusters.

The innovation of synthetic strategies for selective B-H functionalization is a pivotal objective in the realm of boron cluster chemistry. However, the precise, efficient, and rapid functionalization of a B-H bond of carboranes that is distant from the existing functional groups remains intractable owing to the limited approaches for site-selective control from the established methods. Herein, we report a dative bonding activation strategy for the selective functionalization of a nonclassical remote B-H site of nido-carboranes. By leveraging the electronic effects brought by the exopolyhedral B(9)-dative bond, a cross-nucleophile B-H/S-H coupling protocol of the distal B(5)-H bond has been established. The dative bond not only amplifies the subtle reactivity difference among B-H bonds but also significantly changes the reactive sites, further infusing nido-carboranes with additional structural diversity. This reaction paradigm features mild conditions, rapid conversion, efficient production, broad scope, and excellent group tolerance, thus enabling the applicability to an array of complex bioactive molecules. The efficient and scalable reaction platform is amenable to the modular construction of photofunctional molecules and boron delivery agents for boron neutron capture therapy. This work not only provides an unprecedented solution for the selective diversification of distal B-H sites in nido-carboranes but also holds the potential for expediting the discovery of novel carborane-based functional molecules.

Extracellular Vesicles Comprising Carborane Prepared by a Host Exchanging Reaction as a Boron Carrier for Boron Neutron Capture Therapy.

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.

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

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

Albumin nanoparticle electrostatically loaded with highly anionic Gd-thiacalixarene complex for MRI-guided neutron capture therapy

As a neutron capture therapy (NCT) agent, 157Gd garners significant attention due to the largest neutron capture cross section, emission of γ rays and Auger electrons, and facilitation of magnetic resonance imaging-guided NCT. Owing to its high kinetic stability, 1H relaxivity, and facile conjugation to albumin via electrostatic interactions, the negatively charged Gd3TCAS2 complex {TCAS = thiacalix[4]arene-p-tetrasulfonate (TCAS)} was incorporated into albumin nanoparticles (ANPs) in various configurations, including shell, core, and core-shell types, contingent on the positioning of Gd3TCAS2 within the ANP. The characteristics of the ANPs optimized with respect to loading capacity (LC) were explored, all of which demonstrated particle sizes suitable for passive delivery. The LC of Gd3TCAS2 per ANP increased in the following order: shell (1.1 %) < core (1.4 %) < core-shell (8.1 %). The leakage of Gd3TCAS2 after 7 d of storage was approximately 2 % for all ANPs, indicating stable Gd3TCAS2 loading. The 1H relaxivity (e.g., core-shell: r1 = 10.7 mM–1s–1) surpassed that of the Gd3TCAS2 complex alone (3.15 mM–1s–1). The luminescence emanating from Tb in MCF-7 cells co-cultured with Tb3TCAS2-loaded ANPs corroborated this cellular uptake. Gd uptake into MCF-7 cells via Gd3TCAS2-loaded ANPs was most pronounced for core-shell ANP at 1.33 ± 0.06 nmol/106 cells. The cytotoxicity of Gd3TCAS2-loaded ANPs was mitigated compared to free Gd3TCAS2 (CC50 = 52 µM), with shell and core-shell ANPs demonstrating nearly 100 % cell survival even at 50 µM. Cell viability post thermal neutron irradiation revealed the highest NCT efficacy for free Gd3TCAS2, attributed to its elevated cellular uptake (15.71 ± 0.57 nmol/106 cells). Core-shell ANP also exhibited a notable reduction in cell viability relative to the control, validating their potential as a promising GdNCT agent.

Unlocking the potential: phenylboronic acid as a nuclear-targeting boron agent for neutron capture therapy.

It has been proposed that boron neutron capture therapy (BNCT) holds promise as a treatment modality for melanoma. However, the effectiveness of boron agents in delivery remains a critical issue to be addressed for BNCT. To this end, phenylboronic acid, which exhibits good water solubility and low cytotoxicity similar to BPA, has been investigated as a potential nuclear-targeting boron agent. The boron concentration of phenylboronic acid was found to be 74.47 ± 12.17ng/106 B16F10 cells and 45.77 ± 5.64ng/106 cells in the nuclei. Molecular docking experiments were conducted to investigate the binding of phenylboronic acid to importin proteins involved in nuclear transport. The potential of phenylboronic acid to serve as a desirable nucleus-delivery boron agent for neutron capture therapy in melanoma warrants further exploration.

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology.

Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

The Dawn of a New Era: Tumor-Targeting Boron Agents for Neutron Capture Therapy.

Cancer is widely recognized as one of the most devastating diseases, necessitating the development of intelligent diagnostic techniques, targeted treatments, and early prognosis evaluation to ensure effective and personalized therapy. Conventional treatments, unfortunately, suffer from limitations and an increased risk of severe complications. In light of these challenges, boron neutron capture therapy (BNCT) has emerged as a promising approach for cancer treatment with unprecedented precision to selectively eliminate tumor cells. The distinctive and promising characteristics of BNCT hold the potential to revolutionize the field of oncology. However, the clinical application and advancement of BNCT technology face significant hindrance due to the inherent flaws and limited availability of current clinical drugs, which pose substantial obstacles to the practical implementation and continued progress of BNCT. Consequently, there is an urgent need to develop efficient boron agents with higher boron content and specific tumor-targeting properties. Researchers aim to address this need by integrating tumor-targeting strategies with BNCT, with the ultimate goal of establishing BNCT as an effective, readily available, and cutting-edge treatment modality for cancer. This review delves into the recent advancements in integrating tumor-targeting strategies with BNCT, focusing on the progress made in developing boron agents specifically designed for BNCT. By exploring the current state of BNCT and emphasizing the prospects of tumor-targeting boron agents, this review provides a comprehensive overview of the advancements in BNCT and highlights its potential as a transformative treatment option for cancer.

Proposal of recommended experimental protocols for in vitro and in vivo evaluation methods of boron agents for neutron capture therapy.

Recently, boron neutron capture therapy (BNCT) has been attracting attention as a minimally invasive cancer treatment. In 2020, the accelerator-based BNCT with L-BPA (Borofalan) as its D-sorbitol complex (Steboronine®) for head and neck cancers was approved by Pharmaceutical and Medical Devices Agency for the first time in the world. As accelerator-based neutron generation techniques are being developed in various countries, the development of novel tumor-selective boron agents is becoming increasingly important and desired. The Japanese Society of Neutron Capture Therapy believes it is necessary to propose standard evaluation protocols at each stage in the development of boron agents for BNCT. This review summarizes recommended experimental protocols for in vitro and in vivo evaluation methods of boron agents for BNCT based on our experience with L-BPA approval.

New Boron Containing Acridines: Synthesis and Preliminary Biological Study.

The synthesis of the first conjugates of acridine with cobalt bis(dicarbollide) are reported. A novel 9-azido derivative of acridine was prepared through the reaction of 9-methoxyacridine with N3CH2CH2NH2, and its solid-state molecular structure was determined via single-crystal X-ray diffraction. The azidoacridine was used in a copper (I)-catalyzed azide-alkyne cycloaddition reaction with cobalt bis(dicarbollide)-based terminal alkynes to give the target 1,2,3-triazoles. DNA interaction studies via absorbance spectroscopy showed the weak binding of the obtained conjugates with DNA. The antiproliferative activity (IC50) of the boronated conjugates against a series of human cell lines was evaluated through an MTT assay. The results suggested that acridine derivatives of cobalt bis(dicarbollide) might serve as a novel scaffold for the future development of new agents for boron neutron capture therapy (BNCT).

Nanostructured boron agents for boron neutron capture therapy: a review of recent patents.

Boron neutron capture therapy (BNCT) is a potential radiation therapy modality for cancer, and tumor-targeted stable boron-10 (10B) delivery agents are an important component of BNCT. Currently, two low-molecular-weight boron-containing compounds, sodium mercaptoundecahydro-closo-dodecaborate (BSH) and boronophenylalanine (BPA), are mainly used in BNCT. Although both have suboptimal tumor selectivity, they have shown some therapeutic benefit in patients with high-grade glioma and several other tumors. To improve the efficacy of BNCT, great efforts have been devoted for the development of new boron delivery agents with better uptake and favorable pharmacokinetic profiles. This article reviews the application and research progress of boron nanomaterials as boron carriers in boron neutron capture therapy and hopes to stimulate people's interest in nanomaterial-based delivery agents by summarizing various kinds of boron nanomaterial patents disclosed in the past decade.

1,2-Diphenyl-o-carborane and Its Chromium Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Evaluations.

The objective of this study is to design and synthesize substituted η6-chromium(0) tricarbonyl metal complexes carrying o-carborane units as potential boron neutron capture therapy (BNCT) agents. In this study, 1,2-diphenyl-o-carborane (1) units were used as starting materials to generate biologically active species. We investigated how the structural changes of 1 substituted with chromium(0) tricarbonyl affect the biological properties, and 1-(Phenyl-η6-chromium(0) tricarbonyl)-2-phenyl-o-carborane (2) and 1,2-bis(phenyl-η6-chromium(0) tricarbonyl)-o-carborane (3) species were produced in moderate yields. The molecular structures of compounds 1-3 were identified and established by infrared (IR); 1H, 11B, and 13C nuclear magnetic resonance (NMR) and X-ray crystallography analyses. Crystal structures of 1,2-diphenyl-o-carborane and the corresponding chromium complexes 1, 2, and 3 were obtained. In an in vitro study using B16 and CT26 cancer cells containing the triphenyl-o-carboranyl chromium(0) complexes Ph3C2BCr2 and Ph3C2BCr3, which we reported previously, compounds 2 and 3 accumulated at higher levels than compounds Ph3C2BCr2 and Ph3C2BCr3. However, the phenylated o-carboranyl chromium complexes have been found to be more cytotoxic than p-boronophenylalanine (BPA).

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 dueto 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.

A Potential Boron Neutron Capture Therapy Agent Selectively Suppresses High-Grade Glioma: In Vitro and in Vivo Exploration.

Glioblastoma (GBM), as the most central nervous system (CNS) intractable disease, has spoiled millions of lives due to its high mortality. Even though several efforts have been made, the existing treatments have had limited success. In this sense, we studied a lead compound, the boron-rich selective epidermal growth factor receptor (EGFR)-inhibitor hybrid 1, as a potential drug for GBM treatment. For this end, we analyzed the in vitro activity of hybrid 1 in a glioma/primary astrocytes coculture, studying cellular death types triggered by treatment with this compound and its cellular localizations. Additionally, hybrid 1 concentrated boron in glioma cells selectively and more effectively than the boron neutron capture therapy (BNCT)-clinical agent 10B-l-boronophenylalanine and thus displayed a better in vitro-BNCT effect. This encouraged us to analyze hybrid 1 in vivo. Therefore, immunosuppressed mice bearing U87 MG human GBM were treated with both 1 and 1 encapsulated in a modified liposome (recognized by brain-blood barrier peptide transporters), and we observed a potent in vivo per se antitumor activity (tumor size decrease and animal survival increase). These data demonstrate that 1 could be a promising new targeted therapy for GBM.

Lithium halide filled carbon nanocapsules: Paving the way towards lithium neutron capture therapy (LiNCT)

Neutron capture therapy (NCT) is a form of radiotherapy that exploits the potential of some specific isotopes to capture thermal neutrons and subsequently yield high linear energy transfer (LET) particles, suitable for cancer treatment. Recently, relevant technological improvements have been made in terms of accelerators as suitable neutron sources for NCT at hospitals. However, low selective delivery of current drugs to cancer cells remains as the main challenge for successful clinical application of NCT. This work presents an innovative and previously unexplored approach for the design of nanotherapeutic NCT agents. Herein, a new concept based on carbon nanomaterials that seal 6Li active NCT nuclides is investigated. The 6Li active species are located in the inner cavity of the nanocarrier (carbon nanohorns or carbon nanotubes) and therefore, completely protected from the biological environment, avoiding toxicity and degradation. After encapsulation of the active cargo, the external surface of the nanocarrier is modified for improved biocompatibility. The developed 6Li-filled carbon nanohorns offered the possibility to explore 6Li compounds as active NCT agents by delivering therapeutic doses to cancer cells. We envisage that nanoencapsulation of 6Li can trigger the successful development and implementation of Lithium Neutron Cancer Therapy (LiNCT).

Recent Advance in Transition Metal‐Catalyzed Carboxylic Acid Guided B−H Functionalization of Carboranes

AbstractCarboranes, a three‐dimensional class of carbon‐boron molecular clusters with remarkable electronic, physical, chemical characteristics, have proved as useful building blocks in boron neutron capture therapy agents, supramolecular design, optoelectronics, nanomaterials and organometallic/coordination chemistry. Thus, various organic modifications of the B−H and C−H functionalities in carboranes have been developed. These methods with great success utilize directing groups, such as carboxylic acids, to achieve a selective B−H functionalization of carboranes. The carboxyl group can be easily introduced to carboranes and then be removed after reactions. On the other hand, assisted by the carboxyl group a highly regioselective electrophilic attack at the electron‐rich positions B(4) and B(5) of the cage generates five‐membered metallacyclic intermediates, which then undergo further transformation. In this review, we show that transition metal‐catalyzed decarboxylation cross coupling reactions offer an opportunity for the selective and direct B−H activation of carboranes.magnified image

Maleimide-functionalized BODIPY dyes: Synthesis, structural determination and conjugation with carborane thiols

A series of new BODIPY conjugates containing maleimide or carborane-succinimide-triazole functional groups were prepared from synthetically available azido-substituted BODIPYs. The structure of new synthesized compounds was characterized by UV-vis, IR, NMR and mass spectrometry. The crystal structures of BODIPY-maleimide conjugates were determined by single crystal X-ray diffraction study. The carborane-containing BODIPYs can be promising agents for photodynamic and boron neutron capture therapy.

Chitosan-lactobionic acid-thioctic acid-modified hollow mesoporous silica composite loaded with carborane for boron neutron capture therapy of hepatocellular carcinoma

Nanocarriers have been recognized as an effective strategy for developing novel boron-containing delivery agents for boron neutron capture therapy (BNCT) of refractory tumors. Herein, a chitosan-lactobionic acid-thioctic acid-modified hollow mesoporous silica composite loaded with carborane was prepared to achieve effective treatment of hepatocellular carcinoma by BNCT. Notably, the composite remained stable under physiological conditions and exhibited high selective uptake in liver cancer cells. In the tumor microenvironment, the composite could effectively release carborane into the tumor tissue under the dual stimulation of pH and redox. The composite showed excellent efficacy in BNCT treatment of liver cancer cells. Meanwhile, the composite could exert antioxidant and anti-inflammatory effects to reduce the toxic side effects during BNCT. In tumor-bearing mice, the composite could accumulate in tumor tissue with high selectivity. In addition, the composite could be effectively cleared from the normal tissues and could overcome the inflammatory response generated in vivo by the materials in biological applications. Overall, the composite is a promising boron-containing delivery agent in the treatment of hepatocellular carcinoma by BNCT, and can facilitate the biological applications of the silica-like materials in BNCT.