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Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.

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.

Boron (B) is a unique micronutrient for plants given that the range of B concentration from its essentiality to toxicity is extremely narrow, and also because it occurs as an uncharged molecule (boric acid) which can pass lipid bilayers without any degree of controls, as occurs for other ionic nutrients. Boron frequently exceeds the plant’s requirement in arid and semiarid environments due to poor drainage, and in agricultural soils close to coastal areas due to the intrusion of B-rich seawater in fresh aquifer or because of dispersion of seawater aerosol. Global releases of elemental B through weathering, volcanic and geothermal processes are also relevant in enriching B concentration in some areas. Considerable progress has been made in understanding how plants react to B toxicity and relevant efforts have been made to investigate: (I) B uptake and in planta partitioning, (II) physiological, biochemical, and molecular changes induced by B excess, with particular emphasis to the effects on the photosynthetic process, the B-triggered oxidative stress and responses of the antioxidant apparatus to B toxicity, and finally (III) mechanisms of B tolerance. Recent findings addressing the effects of B toxicity are reviewed here, intending to clarify the effect of B excess and to propose new perspectives aimed at driving future researches on the topic.

At the establishment stage of a forest plantation, soil nutritional limitations can lead to insufficient plant growth and predispose plants to biotic and abiotic damages. Adequate plant nutrition contributes to proper plant establishment and subsequent growth. Nitrogen (N) and boron (B), among others, are essential nutrients for plant vigour and growth, and their requirements need to be established. However, there is a lack of information concerning post-transplant fertilisation of stone pine (Pinus pinea L.). The main objective of this work was to evaluate the effect of N and B applications on the vegetative growth of stone pine during the first three years in a conditioned environment. Morphological characteristics such as height growth (HGI), root collar diameter (RCDI), total branches length (TBL) and terminal buds length (BL) were evaluated for each plant, as well as the aboveground and root biomass production. The results showed that N fertilisation caused an increase in all growth variables suggesting that the application of N at a juvenile stage (after transplanting) of this specie will improve its development and obtain a reserve of this nutrient to be used by the plant at later stages of development, especially in soils with low fertility. Boron application had no effect on the evaluated parameters.

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, the United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or “BPA”, and sodium borocaptate or “BSH” (Na 2 B 12 H 11 SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.

BNCT (Boron Neutron Capture Therapy) is a binary radiotherapeutic modality in which high LET (Linear Energy Transfer) particles are generated from 10B(n,α)7Li reaction, ideally within boron-loaded tumour cells, so the therapeutic outcome depends critically on the pharmacokinetics and biodistribution of boron carriers. In this review, boron-containing agents for BNCT, with a focus on ADMET (absorption, distribution, metabolism, excretion and toxicity) and model-informed design, were examined. Low-MW (low-molecular-weight) compounds, peptide conjugates, polymeric and nanostructured platforms and cell-based vectors were surveyed and how physicochemical properties, transporter engagement and nano–bio interactions govern tumour uptake, subcellular localisation and normal tissue exposure were discussed. A shift from maximising boron content towards optimising exposure profiles using PET (Positron Emission Tomography), PBK (physiologically based pharmacokinetic) modelling and in silico ADMET tools to define irradiation windows was also discussed. Classical agents such as BPA (Boronophenylalanine) and BSH (Sodium Borocaptate) are contrasted with newer polymeric and metallacarborane-based carriers, with attention to brain penetration, endosomal escape, linker stability, biodegradation and elimination routes, as well as platform-specific toxicities. Incontestably, further progress in BNCT will highly depend on integrating imaging-derived kinetics with PBPK-informed dose planning and engineering subcellularly precise yet degradable carriers, and that ADMET-guided design and spatiotemporal coordination are central to achieving reproducible clinical benefit from BNCT’s spatial selectivity.

Boron nitride nanotubes (BNNTs) are tubular nanoparticles with a structure analogous to that of carbon nanotubes, but with B and N atoms that completely replace the C atoms. Many favorable results indicate BNNTs as safe nanomaterials; however, important concerns have recently been raised about ultra-pure, long (˜10 µm) BNNTs tested on several cell types. Here, we propose additional experiments with the same BNNTs, but shortened (˜1.5 µm) with a homogenization/sonication treatment that allows for their dispersion in gum Arabic aqueous solutions. Obtained BNNTs are tested on human endothelial and neuron-like cells with several independent biocompatibility assays. Moreover, for the first time, their strong sum-frequency generation signal is exploited to assess the cellular uptake. Our data demonstrate no toxic effects up to concentrations of 20 µg/ml, once more confirming biosafety of BNNTs, and again highlighting that nanoparticle aspect ratio plays a key role in the biocompatibility evaluation. Original submitted 3 December 2013; Revised submitted 28 January 2014; Published online 6 February 2014

New carborane-bearing hydroxamate matrix metalloproteinase (MMP) ligands have been synthesized for boron neutron capture therapy (BNCT) with nanomolar potency against MMP-2, -9 and -13. New analogs are based on MMP inhibitor CGS-23023A, and two previously reported MMP ligands 1 (B1) and 2 (B2) were studied in vitro for BNCT activity. The boronated MMP ligands 1 and 2 showed high in vitro tumoricidal effects in an in vitro BNCT assay, exhibiting IC50 values for 1 and 2 of 2.04 × 10−2 mg/mL and 2.67 × 10−2 mg/mL, respectively. The relative killing effect of 1 to L-boronophenylalanine (BPA) is 0.82/0.27 = 3.0, and that of 2 is 0.82/0.32 = 2.6, whereas the relative killing effect of 4 is comparable to boronophenylalanine (BPA). The survival fraction of 1 and 2 in a pre-incubation boron concentration at 0.143 ppm 10B and 0.101 ppm 10B, respectively, were similar, and these results suggest that 1 and 2 are actively accumulated through attachment to the Squamous cell carcinoma (SCC)VII cells. Compounds 1 and 2 very effectively killed glioma U87 delta EGFR cells after BNCT. This study is noteworthy in demonstrating BNCT efficacy through binding to MMP enzymes overexpressed at the surface of the tumor cell without tumor cell penetration.

A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboranes, and BODIPY, for the treatment of different human diseases.In addition, we also describe the synthesis, key structure–activity relationship, and associated biological activities, such as antimicrobial, antituberculosis, antitumor, antiparasitic, antiprotozoal, anti-inflammatory, antifolate, antidepressant, antiallergic, anesthetic, and anti-Alzheimer’s agents, as well as proteasome and lipogenic inhibitors. This compilation could be very useful in the exploration of novel boron-derived compounds against different diseases, with promising efficacy and lesser side effects.

Boron neutron capture therapy (BNCT) is a binary cancer therapy that involves boron administration and neutron irradiation. The nuclear reaction caused by the interaction of boron atom and neutron produces heavy particles with highly cytocidal effects and destruct tumor cells, which uptake the boron drug. p-Boronophenylalanine (BPA), an amino acid derivative, is used in BNCT. Tumor cells with increased nutrient requirements take up more BPA than normal tissues via the enhanced expression of LAT1, an amino acid transporter. The current study aimed to assess the correlation between the expression of LAT1 and the uptake capacity of BPA using genetically modified LAT1-deficient/enhanced cell lines. We conducted an in vitro study, SCC7 tumor cells wherein LAT1 expression was altered using CRISPR/Cas9 were used to assess BPA uptake capacity. Data from The Cancer Genome Atlas (TCGA) were used to examine the expression status of LAT1 in human tumor tissues, the potential impact of LAT1 expression on cancer prognosis and the potential cancer indications for BPA-based BNCT. We discovered that the strength of LAT1 expression strongly affected the BPA uptake ability of tumor cells. Among the histologic types, squamous cell carcinomas express high levels of LAT1 regardless of the primary tumor site. The higher LAT1 expression in tumors was associated with a higher expression of cell proliferation markers and poorer patient prognosis. Considering that BPA concentrate more in tumors with high LAT1 expression, the results suggest that BNCT is effective for cancers having poor prognosis with higher proliferative potential and nutritional requirements.