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The aim of this review was to define appropriate 11 B delivery agents for boron proton-capture enhanced proton therapy (BPCEPT) taking into account the accumulated knowledge on boron compounds used for boron neutron capture therapy (BNCT). BPCEPT is a promising treatment approach which uses a high linear energy transfer (LET) dose component in conjunction with conventional proton therapy to increase the relative biological effectiveness of highly-selective charged particle therapy. Boron proton fusion reactions occur with highest cross section at certain proton energy level and thus can be tailored to the target volume with careful treatment planning that defines the 675 MeV proton distribution with high accuracy. Appropriate 11 B compounds are required in order to achieve relevant high LET dose contribution from the boron proton-capture reaction. Previous scientific results and experiences with BNCT provide background knowledge and information regarding the optimization of boronated compound development, their characterization, measurement and imaging. However, there are substantial differences between BNCT and BPCEPT, which in turn places special unique chemical, physical and biological demands on 11 B-carrier compounds for BPCEPT. In this review, we evaluate well-known and recently developed boron compounds for BPCEPT., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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.

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

Boron 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.

Among the great variety of anti-cancer therapeutic strategies, boron neutron capture therapy (BNCT) represents a unique approach that doubles the targeting accuracy due to the precise positioning of a neutron beam and the addressed delivery of boron compounds. We have recently demonstrated the principal possibility of using a cell-specific 2′-F-RNA aptamer for the targeted delivery of boron clusters for BNCT. In the present study, we evaluated the amount of boron-loaded aptamer inside the cell via two independent methods: quantitative real-time polymerase chain reaction and inductive coupled plasma–atomic emission spectrometry. Both assays showed that the internalized boron level inside the cell exceeds 1 × 109 atoms/cell. We have synthesized closo-dodecaborate conjugates of 2′-F-RNA aptamers GL44 and Waz, with boron clusters attached either at the 3′- or at the 5′-end. The influence of cluster localization was evaluated in BNCT experiments on U-87 MG human glioblastoma cells and normal fibroblasts and subsequent analyses of cell viability via real-time cell monitoring and clonogenic assay. Both conjugates of GL44 aptamer provided a specific decrease in cell viability, while only the 3′-conjugate of the Waz aptamer showed the same effect. Thus, an individual adjustment of boron cluster localization is required for each aptamer. The efficacy of boron-loaded 2′-F-RNA conjugates was comparable to that of 10B-boronophenylalanine, so this type of boron delivery agent has good potential for BNCT due to such benefits as precise targeting, low toxicity and the possibility to use boron clusters made of natural, unenriched boron. [ABSTRACT FROM AUTHOR]

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/10 6 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.

Boron neutron capture therapy (BNCT) is an attractive approach to treat invasive malignant tumours due to binary heavy-particle irradiation, but its clinical applications have been hindered by boron delivery agents with low in vivo stability, poor biocompatibility, and limited application of combinational modalities. Here, we report boronsome, a carboranyl-phosphatidylcholine based liposome for combinational BNCT and chemotherapy. Theoretical simulations and experimental approaches illustrate high stability of boronsome. Then positron emission tomography (PET) imaging with Cu-64 labelled boronsome reveals high-specific tumour accumulation and long retention with a clear irradiation background. In particular, we show the suppression of tumour growth treated with boronsome with neutron irradiation and therapeutic outcomes are further improved by encapsulation of chemotherapy drugs, especially with PARP1 inhibitors. In sum, boronsome may be an efficient agent for concurrent chemoradiotherapy with theranostic properties against malignancies. Boron neutron capture therapy is a type of cancer therapy but is associated with insufficient boron delivery and with poor biocompatibility. Here, the authors constructed boronated lipids to generate - boronsome - and show the system can reduce tumour growth. [ABSTRACT FROM AUTHOR]

Drug leads with a high Fsp3 index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the first detailed NMR analysis of the borylated intermediate 3-deoxy-3-boronodiethanolamine-1,2:5,6-di-O-isopropylidene-α-d-galactofuranose and of the corresponding free monosaccharide analogue 3-boronic-3-deoxy-d-galactose in the early stage of the concurrent equilibrium processes of mutarotation and borarotation. A discussion of all potential equilibria is also presented alongside a comparison with relevant 11B-NMR data available from the scientific literature and our own library. [ABSTRACT FROM AUTHOR]

Heteropolycyclic molecular systems, which are essential components in the fields of materials and pharmacology, frequently consist of 2D extended organic aromatic rings. Here, we introduce a type of inorganic-organic hybrid 3D conjugates by merging an aromatic boron cluster with a phosphine and a π-conjugated unit. To achieve this, a couple-close synthetic strategy via B–H activation of nido-carboranes with alkynes has been developed, which leads to diverse boron cluster-extended phosphoniums in a twisted structure with high yields under mild conditions. Experimental and theoretical results reveal that the fusion between the boron cluster and the formed borophosphonium heterocycle facilitates electron delocalization throughout the structure. The unusual framework demonstrates distinct properties from bare boron clusters and pure aromatic ring-extended counterparts, such as improved thermal/chemical stability and photophysical properties. Thus, the boron cluster-based 3D conjugates expand the library of aromatic-based heterocyclics, showcasing great potential in functional materials. 2D π-conjugated systems incorporated with heteroatoms can suffer from stability issues and aggregation-induced quenching effects. Here, the authors develop a methodology for the synthesis of cluster-ring-fused 3D aromatic heterocycles, which could find use in functional materials, via the palladium-catalyzed B–H activation of boron clusters. [ABSTRACT FROM AUTHOR]

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

Boron neutron capture therapy (BNCT) is a binary type of radiotherapy for the treatment of cancer. Due to recent developments of neutron accelerators and their installation in some hospitals, BNCT is on the rise worldwide and is expected to have a significant impact on patient treatments. Therefore, there is an increasing need for improved boron delivery agents. Among the many small molecules and delivery systems developed, a significant amount of recent research focused on the synthesis of boron-containing sugar and amino acid derivatives to exploit specific transport proteins, as d-glucose transporter 1 (GLUT1) and large neutral amino acid transporter (LAT1), overexpressed by tumor cells. This review will discuss the last year's achievements in the synthesis and some biological evaluation of boronated sugars derivatives. The compounds described in this review are intrinsically asymmetric due to the presence of chiral sugar moieties, often joined to boron clusters, which are structural elements with high symmetry. [ABSTRACT FROM AUTHOR]

Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 (10B) in the oral mucosa to the biological effectiveness of the 10B(n,alpha)7Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 +/- 0.02. This compares with a previously published CBE factor for BPA of 4.87 +/- 0.16. It was concluded that variations in the microdistribution profile of 10B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiation-induced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT.

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

Boron neutron capture therapy (BNCT) is one of the most appealing radiotherapy modalities, whose localization can be further improved by the employment of boron-containing nanoformulations, but the fabrication of biologically friendly, water-dispersible nanoparticles (NPs) with high boron content and favorable physicochemical characteristics still presents a great challenge. Here, we explore the use of elemental boron (B) NPs (BNPs) fabricated using the methods of pulsed laser ablation in liquids as sensitizers of BNCT. Depending on the conditions of laser-ablative synthesis, the used NPs were amorphous (a-BNPs) or partially crystallized (pc-BNPs) with a mean size of 20 nm or 50 nm, respectively. Both types of BNPs were functionalized with polyethylene glycol polymer to improve colloidal stability and biocompatibility. The NPs did not initiate any toxicity effects up to concentrations of 500 µg/mL, based on the results of MTT and clonogenic assay tests. The cells with BNPs incubated at a 10B concentration of 40 µg/mL were then irradiated with a thermal neutron beam for 30 min. We found that the presence of BNPs led to a radical enhancement in cancer cell death, namely a drop in colony forming capacity of SW-620 cells down to 12.6% and 1.6% for a-BNPs and pc-BNPs, respectively, while the relevant colony-forming capacity for U87 cells dropped down to 17%. The effect of cell irradiation by neutron beam uniquely was negligible under these conditions. Finally, to estimate the dose and regimes of irradiation for future BNCT in vivo tests, we studied the biodistribution of boron under intratumoral administration of BNPs in immunodeficient SCID mice and recorded excellent retention of boron in tumors. The obtained data unambiguously evidenced the effect of a neutron therapy enhancement, which can be attributed to efficient BNP-mediated generation of α-particles. [ABSTRACT FROM AUTHOR]

Most treatment planning systems of boron neutron capture therapy perform dose calculations based on the assumption of a homogeneous boron distribution in tumors, which leads to dose distortion due to the difference between the tumor-to-normal tissue ratio (TNR) range measured in positron emission tomography images (PET) and the target delineation in computed tomography images of the treatment plan. The heterogeneous boron distribution in the target of the treatment plan can be obtained by image fusion. This study provides a way to quantify a heterogeneous boron distribution based on PET images. Theoretically, the same mean TNR for dose calculation by homogeneous or heterogeneous boron distribution should get almost the same mean dose. However, slightly different mean doses are found due to the partial volume effect for a small target volume. The wider the boron distribution is, the higher the impact on the dose-volume histogram distribution is. Dose distribution with homogeneous boron distribution may be overestimated in low boron uptake regions by wrong boron concentration and neutron flux depression. To accurately give the tumor prescription dose and achieve better tumor control, for low dose regions of the tumor should be considered more boron neutron capture therapy treatments or combined with other treatment modalities. The heterogeneous boron distribution must be taken into consideration to have an accurate dose estimation. Therefore, the way how medical physicists and clinicians process the TNR in gross tumor volume should be refined, and the method demonstrated in the work provides a good reference. [ABSTRACT FROM AUTHOR]

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

Mixed-ligand lead(II) complexes with 2,2′-bipyridyl and [B10H9OH]2− or monosubstituted hydroxy-substituted closo-decaborate anions with a pendant hydroxy group, separated from the boron cage by an alkoxylic spacer of different lengths [B10H9O(CH2)xO(CH2)2OH]]2− (x = 2 or 5) have been synthesized. Compounds have been characterized by IR and multinuclear NMR spectroscopies. The structures of binuclear complex [Pb(bipy)2[B10H9OH]]2·CH3CN (1·CH3CN), mononuclear complex [Pb(bipy)2[B10H9O(CH2)2O(CH2)2OH]]·0.5bipy·CH3CN (2·0.5bipy·CH3CN), and polymeric complex [Pb(bipy)[B10H9O(CH2)5O(CH2)2OH]]n (3) have been determined by single-crystal X-ray diffraction. In all three compounds, the co-ordination polyhedra of lead(II) are formed by N atoms from two bipy molecules, O atoms of the substituent attached to the boron cage, and BH groups of the boron cage. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of a novel boron carrier is a key step in clinical boron neutron capture therapy (BNCT). We previously reported that maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) with albumin as the drug delivery system is an effective boron carrier for the F98 glioma-bearing rat brain tumor model. In this study, the efficacy of BNCT with cRGD-MID-AC, a cyclic arginine-glycine-aspartate (cRGD) targeting integrin αvβ3 added to MID-AC, was evaluated in a glioma-bearing rat brain tumor model. Although the cellular boron concentration of cRGD-MID-AC was lower than that of boronophenylalanine (BPA), in vitro neutron-irradiation experiments confirmed that the cell-killing effect of BNCT using cRGD-MID-AC was similar to that of BNCT using BPA. In vivo biodistribution showed a sufficient boron concentration in the tumor after intravenous administration. In neutron-irradiation experiments, the BNCT group using cRGD-MID-AC showed significantly prolonged survival compared to the untreated group, and long-term survivors were observed. This drug shows promise as a novel agent for BNCT. Integrin αvβ3 is more highly expressed in high-grade glioma cells than in normal tissues. In this study, a novel boron-10 carrier containing maleimide-functionalized closo-dodecaborate (MID), serum albumin as a drug delivery system, and cyclic arginine-glycine-aspartate (cRGD) that can target integrin αvβ3 was developed. The efficacy of boron neutron capture therapy (BNCT) targeting integrin αvβ3 in glioma cells in the brain of rats using a cRGD-functionalized MID-albumin conjugate (cRGD-MID-AC) was evaluated. F98 glioma cells exposed to boronophenylalanine (BPA), cRGD-MID-AC, and cRGD + MID were used for cellular uptake and neutron-irradiation experiments. An F98 glioma-bearing rat brain tumor model was used for biodistribution and neutron-irradiation experiments after BPA or cRGD-MID-AC administration. BNCT using cRGD-MID-AC had a sufficient cell-killing effect in vitro, similar to that with BNCT using BPA. In biodistribution experiments, cRGD-MID-AC accumulated in the brain tumor, with the highest boron concentration observed 8 h after administration. Significant differences were observed between the untreated group and BNCT using cRGD-MID-AC groups in the in vivo neutron-irradiation experiments through the log-rank test. Long-term survivors were observed only in BNCT using cRGD-MID-AC groups 8 h after intravenous administration. These findings suggest that BNCT with cRGD-MID-AC is highly selective against gliomas through a mechanism that is different from that of BNCT with BPA. [ABSTRACT FROM AUTHOR]

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

Boron neutron capture therapy is a low-invasive cancer therapy based on the neutron fission process that occurs upon thermal neutron irradiation of 10B-containing compounds; this process causes the release of alpha particles that selectively damage cancer cells. Although several clinical studies involving mercaptoundecahydro-closo-dodecaborate and the boronophenylalanine–fructose complex are currently ongoing, the success of this promising anticancer therapy is hampered by the lack of appropriate drug delivery systems to selectively carry therapeutic concentrations of boron atoms to cancer tissues, allowing prolonged boron retention therein and avoiding the damage of healthy tissues. To achieve these goals, numerous research groups have explored the possibility to formulate nanoparticulate systems for boron delivery. In this review. we report the newest developments on boron vehiculating drug delivery systems based on nanoparticles, distinguished on the basis of the type of carrier used, with a specific focus on the formulation aspects. [ABSTRACT FROM AUTHOR]

BNCT is a non-invasive cancer therapy that allows for cancer cell death without harming adjacent cells. However, the application is limited, owing to the challenges of working with clinically approved boron (B) compounds and drug delivery systems (DDS). To address the issues, we developed self-forming nanoparticles consisting of a biodegradable polymer, namely, "AB-type Lactosome (AB-Lac)" loaded with B compounds. Three carborane isomers (o-, m-, and p-carborane) and three related alkylated derivatives, i.e., 1,2-dimethy-o-carborane (diC1-Carb), 1,2-dihexyl-o-carborane (diC6-Carb), and 1,2-didodecyl-o-carborane (diC12-Carb), were separately loaded. diC6-Carb was highly loaded with AB-Lac particles, and their stability indicated the "molecular glue" effect. The efficiency of in vitro B uptake of diC6-Carb for BNCT was confirmed at non-cytotoxic concentration in several cancer cell lines. In vivo/ex vivo biodistribution studies indicated that the AB-Lac particles were remarkably accumulated within 72 h post-injection in the tumor lesions of mice bearing syngeneic breast cancer (4T1) cells, but the maximum accumulation was reached at 12 h. In ex vivo B biodistribution, the ratios of tumor/normal tissue (T/N) and tumor/blood (T/Bl) of the diC6-Carb-loaded particles remained stably high up to 72 h. Therefore, we propose the diC6-Carb-loaded AB-Lac particles as a promising candidate medicine for BNCT. [ABSTRACT FROM AUTHOR]

This study was performed to investigate the biological effects of boron neutron capture therapy (BNCT) on the testes and eyes in mice using HANARO Nuclear Reactor, Korea Atomic Energy Research Institute. BNCT relies on the high capacity of 10B in capturing thermal neutrons. Sodium borocaptate (BSH, 75 ppm, iv) and boronophenylalanine (BPA, 750 ppm, ip) have been used as the boron delivery agents. Mice were irradiated with neutron (flux: 1.036739E +09, Fluence 9.600200E+12) by lying flat pose for 30 (10 Gy) or 100 min (33 Gy) with or without boron carrier treatment. In 45 days of irradiation, histopathological changes of the testes and eyes were examined. Thirty-three Gy neutron irradiation for 100 min induced testicular atrophy in which some of seminiferous tubules showed complete depletion of spermatogenic germ cells. Lens epithelial cells and lens fiber were swollen and showed granular changes in an exposure time dependent manner. However, boron carrier treatment had no significant effect on the lesions. These results suggest that the examination of histopathological changes of lens and testis can be used as "biological dosimeters" for gauging radiation responses and the HANARO Nuclear Reactor has sufficient capacities for the BNCT. [ABSTRACT FROM AUTHOR]

Sufficient boron-10 isotope (10B) accumulation by tumor cells is one of the main requirements for successful boron neutron capture therapy (BNCT). The inability of the clinically registered 10B-containing borophenylalanine (BPA) to maintain a high boron tumor concentration during neutron irradiation after a single injection has been partially solved by its continuous infusion; however, its lack of persistence has driven the development of new compounds that overcome the imperfections of BPA. We propose using elemental boron nanoparticles (eBNPs) synthesized by cascade ultrasonic dispersion and destruction of elemental boron microparticles and stabilized with hydroxyethylcellulose (HEC) as a core component of a novel boron drug for BNCT. These HEC particles are stable in aqueous media and show no apparent influence on U251, U87, and T98G human glioma cell proliferation without neutron beam irradiation. In BNCT experiments, cells incubated with eBNPs or BPA at an equivalent concentration of 40 µg 10B/mL for 24 h or control cells without boron were irradiated at an accelerator-based neutron source with a total fluence of thermal and epithermal neutrons of 2.685, 5.370, or 8.055 × 1012/cm2. The eBNPs significantly reduced colony-forming capacity in all studied cells during BNCT compared to BPA, verified by cell-survival curves fit to the linear-quadratic model and calculated radiobiological parameters, though the effect of both compounds differed depending on the cell line. The results of our study warrant further tumor targeting-oriented modifications of synthesized nanoparticles and subsequent in vivo BNCT experiments. [ABSTRACT FROM AUTHOR]

Simple Summary: The blood–brain barrier (BBB) is formed by the brain capillary endothelium and prevents almost all therapeutic agents from reaching the brain. The importance of the BBB in brain tumor treatments has not been recognized until recently, including in the case of boron neutron capture therapy (BNCT), although it affects therapeutic efficacy when treating brain tumors. Recently, some drug delivery systems to bypass the BBB have been developed for brain tumor therapy, and our laboratory has been developing a system for boron delivery to brain cells using cerebrospinal fluid (CSF) circulation, which we call the "boron CSF administration method". In this study, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. As a result, we found that boron injected using the CSF administration method accumulates to high levels in tumor cells, with a high T/N ratio. In addition, the dose required for the boron drug was much lower than that used in the intravenous (IV) administration method for equivalent effects. This approach makes it possible for clinicians to inject a lower drug dose into patient, thus reducing the potential side effects of excessive amounts of the drug and decreasing its cost. We hope our findings will inspire additional studies on boron delivery to brain tumors for BNCT. Recently, exploitation of cerebrospinal fluid (CSF) circulation has become increasingly recognized as a feasible strategy to solve the challenges involved in drug delivery for treating brain tumors. Boron neutron capture therapy (BNCT) also faces challenges associated with the development of an efficient delivery system for boron, especially to brain tumors. Our laboratory has been developing a system for boron delivery to brain cells using CSF, which we call the "boron CSF administration method". In our previous study, we found that boron was efficiently delivered to the brain cells of normal rats in the form of small amounts of L-p-boronophenylalanine (BPA) using the CSF administration method. In the study described here, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. We first investigated the boron concentration of the brain cells every 60 min after BPA administration into the lateral ventricle of normal rats. Second, we measured and compared the boron concentration in the melanoma model rats after administering boron via either the CSF administration method or the intravenous (IV) administration method, with estimation of the T/N ratio. Our results revealed that boron injected by the CSF administration method was excreted quickly from normal cells, resulting in a high T/N ratio compared to that of IV administration. In addition, the CSF administration method resulted in high boron accumulation in tumor cells. In conclusion, we found that using our developed CSF administration method results in more selective delivery of boron to the brain tumor compared with the IV administration method. [ABSTRACT FROM AUTHOR]

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

The application of boron neutron capture therapy (BNCT) mediated by liposomes containing 10B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the hamster cheek pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH3(CH2)15-7,8-C2B9H11] (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na3[ae-B20H17NH3] (TAC) in the aqueous core. Unilamellar liposomes with a mean diameter of 83 nm were administered i.v. in hamsters. After 48 h, the boron concentration in tumors was 67 ± 16 ppm whereas the precancerous tissue contained 11 ± 6 ppm, and the tumor/normal pouch tissue boron concentration ratio was 10:1. Neutron irradiation giving a 5-Gy dose to precancerous tissue (corresponding to 21 Gy in tumor) resulted in an overall tumor response (OR) of 70% after a 4-wk posttreatment period. In contrast, the beam-only protocol gave an OR rate of only 28%. Once-repeated BNCT treatment with readministration of liposomes at an interval of 4, 6, or 8 wk resulted in OR rates of 70-88%, of which the complete response ranged from 37% to 52%. Because of the good therapeutic outcome, it was possible to extend the follow-up of BNCT treatment groups to 16 wk after the first treatment. No radiotoxicity to normal tissue was observed. A salient advantage of these liposomes was that only mild mucositis was observed in dose-limiting precancerous tissue with a sustained tumor response of 70-88%. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of 10B atoms required for their capture/irradiation with low-energy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly- l-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots) to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a cancer treatment with clinically demonstrated efficacy using boronophenylalanine (BPA) and sodium mercaptododecaborate (BSH). However, tumor tissue selectivity of BSH and retention of BPA in tumor cells is a constant problem. To ensure boron accumulation and retention in tumor tissues, we designed a novel polyethylene glycol (PEG)-based boron-containing lipid (PBL) and examined the potency of delivery of boron using novel PBL-containing liposomes, facilitated by the enhanced permeability and retention (EPR) effect. PBL was synthesized by the reaction of distearoylphosphoethanolamine and BSH linked by PEG with Michael addition while liposomes modified using PBL were prepared from the mixed lipid at a constant molar ratio. In this manner, novel boron liposomes featuring BSH in the liposomal surfaces, instead of being encapsulated in the inner aqueous phase or incorporated in the lipid bilayer membrane, were prepared. These PBL liposomes also carry additional payload capacity for more boron compounds (or anticancer agents) in their inner aqueous phase. The findings demonstrated that PBL liposomes are promising candidates to effect suitable boron accumulation for BNCT. [ABSTRACT FROM AUTHOR]

In this work, we synthetized and characterized new crystalline materials with theranostic properties, i.e., they can be used both as bio-sensors and for "drug delivery". The two solid crystalline compounds studied are Metal Organic Frameworks and have formulas Li[(C6H12O6)2B]·2H2O and Li[(C4H2O6)2B]·5.5H2O. They can be synthetized both with natural isotopes of Li and B or with 6Li and 10B isotopes, that can be explored for Neutron Capture Therapy (NCT) for anti-cancer treatment. The presence of chiral organic molecules, such as mannitol and tartaric acid, provides the NLO property to the crystals and thus their capability to generate the Second Harmonic, which is useful for applications as bio-sensors. The two compounds were characterized with X-ray Diffraction and the Second Harmonic Generation (SHG) responses were estimated by theoretical calculations, and the results were compared with experimental measurements of powdered samples. In order to test the behavior of such compounds under thermal neutron irradiation, we preliminary exposed one of the two compounds in the e_LiBANS facility at the Torino Physics Department. Preliminary results are reported. [ABSTRACT FROM AUTHOR]