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This article briefly reviews the development of boron delivery agents used in boron neutron capture therapy from the 1950s to the present, and highlights the booming third-generation boron delivery agents. Since the 1950s, boron delivery agents has gradually experienced three generations of development. The first generation of boric acid analogs withdrew from the historical stage due to lack of tumor specificity; the second generation of BPA and BSH have passed the historical test and become the only two currently used in clinics, playing an important role in the treatment of locally invasive malignant tumors such as melanoma, gliomas, and recurrent head and neck cancer; the third generation of boron delivery agents are constantly challenging BPA and BSH in a blooming manner. In pursuit of better treatment effects, the new boron carrier agent that is constantly exploring in the direction of integration of diagnosis and treatment and diversification will create new possibilities for boron neutron capture therapy.

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.

The aim of this review was to define appropriate 11B 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 11B 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 11B-carrier compounds for BPCEPT. In this review, we evaluate well-known and recently developed boron compounds for BPCEPT.

Unnatural cyclic amino acids (UNAAs) are a new class of boron delivery agents that are in a pre-clinical stage of evaluation. In the present study, the biodistribution of racemic forms of the cis- and trans-isomers of the boronated UNAA 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) and 1-amino-3-boronocycloheptanecarboxylic acid (ABCHC) were evaluted in B16 melanoma bearing mice and this was compared to l -p-boronophenylalanine (BPA). Boron concentrations were determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) at 2.5 h following intraperitoneal (i.p.) injection of the test agents at a concentration equivalent to 24 mg/B/kg. While all compounds attained comparable tumor boron concentrations, the tumor/blood (T/Bl) boron concentration ratios were far superior for both cis-ABCPC and cis-ABCHC compared to BPA (T/Bl=16.4, and 15.1 vs. 5.4). Secondary ion mass spectrometry (SIMS) imaging revealed that the cis-ABCPC delivered boron to the nuclei, as well as the cytoplasm of B16 cells. Next, a biodistribution study of cis-ABCPC and BPA was carried out in F98 glioma bearing rats following i.p. administration. Both compounds attained comparable tumor boron concentrations but the tumor/brain (T/Br) boron ratio was superior for cis-ABCPC compared to BPA (6 vs. 3.3). Since UNAAs are water soluble and cannot be metabolized by tumor cells, they could be potentially more effective boron delivery agents than BPA. Our data suggest that further studies are warranted to evaluate these compounds prior to the initiation of clinical studies.

3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 ((10)B) delivery agent for neutron capture therapy (NCT). N5-2OH is an excellent substrate of thymidine kinase 1 and its favorable biodistribution profile in rodents led to successful preclinical NCT of rats bearing intracerebral RG2 glioma. The present study explored cellular influx and efflux mechanisms of N5-2OH, as well as its intracellular anabolism beyond the monophosphate level. N5-2OH entered cultured human CCRF-CEM cells via passive diffusion, whereas the multidrug resistance-associated protein 4 appeared to be a major mediator of N5-2OH monophosphate efflux. N5-2OH was effectively monophosphorylated in cultured murine L929 [thymidine kinase 1 (TK1(+))] cells whereas formation of N5-2OH monophosphate was markedly lower in L929 (TK1(-)) cell variants. Further metabolism to the di- and triphosphate forms was not observed in any of the cell lines. Regardless of monophosphorylation, parental N5-2OH was the major intracellular component in both TK1(+) and TK1(-) cells. Phosphate transfer experiments with enzyme preparations showed that N5-2OH monophosphate, as well as the monophosphate of a second 3-carboranyl thymidine analog [3-[5-(o-carboran-1-yl)pentan-1-yl]thymidine (N5)], were not substrates of thymidine monophosphate kinase. Surprisingly, N5-diphosphate was phosphorylated by nucleoside diphosphate kinase although N5-triphosphate apparently was not a substrate of DNA polymerase. Our results provide valuable information on the cellular metabolism and pharmacokinetic profile of 3-carboranyl thymidine analogs.

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.

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.

Combination therapy is becoming an increasingly important treatment strategy because multi-drugs can maximize therapeutic effect and overcome potential mechanisms of drug resistance. A new albumin-based theranostic containing gemcitabine closo-dodecaborate analogue has been developed for combining boron neutron capture therapy (BNCT) and chemotheraphy. An exo-heterocyclic amino group of gemcitabine was used to introduce closo-dodecaborate, and a 5′-hydroxy group was used to tether maleimide moiety through an acid-labile phosphamide linker. The N-trifluoroacylated homocysteine thiolactone was used to attach the gemcitabine analogue to human serum albumin (HSA) bearing Cy5 or Cy7 fluorescent dyes. The half-maximal inhibitory concentration (IC50) of the designed theranostic relative to T98G cells was 0.47 mM with the correlation coefficient R = 0.82. BNCT experiments resulted in a decrease in the viability of T98G cells, and the survival fraction was ≈ 0.4.

There is an incontestable need for improved treatment modality for glioblastoma due to its extraordinary resistance to traditional chemoradiation therapy. Boron neutron capture therapy (BNCT) may play a role in the future. We designed and synthesized a 10B-boronated derivative of temozolomide, TMZB. BNCT was carried out with a total neutron radiation fluence of 2.4 ± 0.3 × 1011 n/cm2. The effects of TMZB in BNCT were measured with a clonogenic cell survival assay in vitro and PET/CT imaging in vivo. Then, 10B-boronated phenylalanine (BPA) was tested in parallel with TMZB for comparison. The IC50 of TMZB for the cytotoxicity of clonogenic cells in HS683 was 0.208 mM, which is comparable to the IC50 of temozolomide at 0.213 mM. In BNCT treatment, 0.243 mM TMZB caused 91.2% ± 6.4% of clonogenic cell death, while 0.239 mM BPA eliminated 63.7% ± 6.3% of clonogenic cells. TMZB had a tumor-to-normal brain ratio of 2.9 ± 1.1 and a tumor-to-blood ratio of 3.8 ± 0.2 in a mouse glioblastoma model. BNCT with TMZB in this model caused 58.2% tumor shrinkage at 31 days after neutron irradiation, while the number for BPA was 35.2%. Therefore, by combining the effects of chemotherapy from temozolomide and radiotherapy with heavy charged particles from BNCT, TMZB-based BNCT exhibited promising potential for therapeutic applications in glioblastoma treatment.

Boron neutron capture therapy is a unique form of adjuvant cancer therapy for various malignancies including malignant gliomas. The conjugation of boron compounds and human serum albumin (HSA)—a carrier protein with a long plasma half-life—is expected to extend systemic circulation of the boron compounds and increase their accumulation in human glioma cells. We report on the synthesis of fluorophore-labeled homocystamide conjugates of human serum albumin and their use in thiol-‘click’ chemistry to prepare novel multimodal boronated albumin-based theranostic agents, which could be accumulated in tumor cells. The novelty of this work involves the development of the synthesis methodology of albumin conjugates for the imaging-guided boron neutron capture therapy combination. Herein, we suggest using thenoyltrifluoroacetone as a part of an anticancer theranostic construct: approximately 5.4 molecules of thenoyltrifluoroacetone were bound to each albumin. Along with its beneficial properties as a chemotherapeutic agent, thenoyltrifluoroacetone is a promising magnetic resonance imaging agent. The conjugation of bimodal HSA with undecahydro-closo-dodecaborate only slightly reduced human glioma cell line viability in the absence of irradiation (~30 μM of boronated albumin) but allowed for neutron capture and decreased tumor cell survival under epithermal neutron flux. The simultaneous presence of undecahydro-closo-dodecaborate and labeled amino acid residues (fluorophore dye and fluorine atoms) in the obtained HSA conjugate makes it a promising candidate for the combination imaging-guided boron neutron capture therapy.

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.

Статья знакомит с методом бор-нейтронзахватной терапии (БНЗТ) и возможностями ее клинического применения для лечения опухолей головного мозга. Приводятся анализ и обзор данных литературы о БНЗТ, а также статистика выживаемости пациентов. Дается сравнительная характеристика различных источников нейтронов, используемых для этого метода лечения. Рассматривается решение двух проблем клинического внедрения БНЗТ: создание автономного источника эпитепловых нейтронов и избирательной доставки бор-содержащих препаратов к центральной нервной системе. Анализ решения данных проблем дополняется результатами разработок и экспериментальными данными лаборатории БНЗТ Института ядерной физики СО РАН., The article introduces the method of boron neutron capturing therapy (BNCT) and its potential clinical application for treatment of malignant brain tumors. The analysis and literature review of the use of BNCT in the world, citing statistics on the survival rate of patients with brain tumor after a session of BNCT. Comparative characteristics of various neutron sources used for BNCT in the world. A review of pharmacological agents used in BNCT as a delivery agent 10B. Based on the review of the literature produced outlining the recognized problems of the method. We consider the two challenges for clinical implementation of BNCT create an independent source of epithermal neutrons and selective delivery of boron-containing drugs to the central nervous system. Analysis of the solution of these difficulties is complemented by the results of development and experimental data of the laboratory of BNCT of Budker Institute of Nuclear Physics.

Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (10B) nuclei that have entered tumor cells to produce highly linear energy transfer (LET) alpha particles and recoil 7Li nuclei (10B [n, α] 7Li). Therefore, the most important part in BNCT is to selectively deliver a large number of 10B to tumor cells and only a small amount to normal tissue. So far, BNCT has been used in more than 2000 cases worldwide, and the efficacy of BNCT in the treatment of head and neck cancer, malignant meningioma, melanoma and hepatocellular carcinoma has been confirmed. We collected and collated clinical studies of second-generation boron delivery agents. The combination of different drugs, the mode of administration, and the combination of multiple treatments have an important impact on patient survival. We summarized the critical issues that must be addressed, with the hope that the next generation of boron delivery agents will overcome these challenges.

Boron Neutron Capture Therapy (BNCT) is a new binary radiation therapy for tumor tissue, which kills tumor cells with neutron capture reaction. Boron neutron capture therapy has become a technical means for glioma, melanoma, and other diseases has been included in the clinical backup program. However, BNCT is faced with the key problem of developing and innovating more efficient boron delivery agents to solve the targeting and selectivity. We constructed a tyrosine kinase inhibitor-L-p-boronophenylalanine (TKI-BPA) molecule, aiming to improve the selectivity of boron delivery agents by conjugating targeted drugs while increasing the molecular solubility by adding hydrophilic groups. It shows excellent selectivity in differential uptake of cells, and its solubility is more than 6 times higher than BPA, leading to the saving of boron delivery agents. This modification method is effective for improving the efficiency of the boron delivery agent and is expected to become a potential alternative with high clinical application value.

The development of new accelerators has given a new impetus to the development of new drugs and treatment technologies using boron neutron capture therapy (BNCT). We analyzed the current status and future directions of BNCT for cancer treatment, as well as the main issues related to its introduction. This review highlights the principles of BNCT and the key milestones in its development: new boron delivery drugs and different types of charged particle accelerators are described; several important aspects of BNCT implementation are discussed. BCNT could be used alone or in combination with chemotherapy and radiotherapy, and it is evaluated in light of the outlined issues. For the speedy implementation of BCNT in medical practice, it is necessary to develop more selective boron delivery agents and to generate an epithermal neutron beam with definite characteristics. Pharmacological companies and research laboratories should have access to accelerators for large‐scale screening of new, more specific boron delivery agents.

Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (4He) and recoil lithium particles (7Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.

BNCT is an alternate therapy for treating cancer. The principle of BNCT involves a neutron boron uptake and a fission reaction that produce alpha particles and Li ions with a high level of linear energy transfer in the tissue. It is effective in killing tumor cells. To administer boron in the tumor cells, a boron delivery agent is needed. Thus far, there are a variety of boron delivery agents that have been developed. To date, just two main boron-based drugs, BPA and BSH, have been used for clinical studies. Many other boron delivery agents have been evaluated in vivo and in vitro but have not been evaluated clinically. Therefore, the other boron delivery agents have not been used in BNCT clinical studies.

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.

Each year more than 3,000 Canadians are diagnosed with brain cancers like glioblastoma multiforme or recurrent head and neck cancers which are difficult to treat with conventional radiotherapy techniques. One of the most clinically promising treatments for these cancers is boron neutron capture therapy (BNCT). This procedure involves selectively introducing a boron delivery agent into tumor cells and irradiating them with a neutron beam, which kills the cancer cells due to the high-LET radiation produced by the 10B(n,α)7Li capture reaction. The theory of BNCT has been around for a long time since 1936, but has historically been limited by poor boron delivery agents and nonoptimal neutron source facilities. Although significant improvements have been made in both of these domains, it is mainly the advancements of accelerator-based neutron sources that has led to the expansion of over 20 new BNCT facilities worldwide in the past decade. Additionally in this work, PHITS (Particle and Heavy Ion Transport Code System) simulations, in collaboration with the University of Tsukuba, were performed to examine the effectiveness of the Ibaraki-Boron Neutron Capture Therapy (iBNCT) beam shaping assembly (BSA) to moderate a neutron beam suitable for BNCT at the proposed PC-CANS (Prototype Canadian Compact Accelerator-based Neutron Source) site, which uses a similar but slightly higher energy 10 MeV proton accelerator with a 1 mA average current. The advancements of compact acceleratorbased neutron sources in recent decades has enabled significant improvements in BNCT technologies, allowing it to become a more viable clinical treatment option.

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,α)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. © 2000 Cancer Research Campaign

Boron neutron capture therapy (BNCT) is a re-emerging technique for selectively killing tumor cells. Briefly, the mechanism can be described as follows: after the uptake of boron into cells, the thermal neutrons trigger the fission of the boron atoms, releasing the α-particles and recoiling lithium particles and high-energy photons that damage the cells. We performed a detailed study of the reactor dosimetry, cellular dose assessment, and radiobiological effects induced by BNCT in glioblastoma (GBM) cells. At maximum reactor power, neutron fluence rates were ϕ0 = 6.6 × 107 cm−2 s−1 (thermal) and θ = 2.4 × 104 cm−2 s−1 with a photon dose rate of 150 mGy·h−1. These values agreed with simulations to within 85% (thermal neutrons), 78% (epithermal neutrons), and 95% (photons), thereby validating the MCNPX model. The GEANT4 simulations, based on a realistic cell model and measured boron concentrations, showed that >95% of the dose in cells was due to the BNC reaction. Carboranylmethylbenzo[b]acridone (CMBA) is among the different proposed boron delivery agents that has shown promising properties due to its lower toxicity and important cellular uptake in U87 glioblastoma cells. In particular, the results obtained for CBMA reinforce radiobiological effects demonstrating that damage is mostly induced by the incorporated boron with negligible contribution from the culture medium and adjacent cells, evidencing extranuclear cell radiosensitivity.

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.

Background: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer α particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. Boron Delivery Agents: Two boron drugs have been used clinically, sodium borocaptate (Na2B12H11SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations (∼20 μg/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boron-containing amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. Clinical Trials: Current or recently completed clinical trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of “debulking” surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v. have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established. Conclusions: Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with10 B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT. Much of the complexity has been unravelled through a combination of preclinical experimentation and clinical dose escalation experience. Over 350 patients have been treated in a number of different facilities worldwide. The accumulated clinical experience has demonstrated that BNCT can be delivered safely but is still defining the limits of normal brain tolerance. Several independent BNCT clinical protocols have demonstrated that BNCT can produce median survivals in patients with glioblastoma that appear to be equivalent to conventional photon therapy. This review describes the individual components and methodologies required for effect BNCT: the boron delivery agents; the analytical techniques; the neutron beams; the dosimetry and radiation biology measurements; and how these components have been integrated into a series of clinical studies. The single greatest weakness of BNCT at the present time is non-uniform delivery of boron into all tumor cells. Future improvements in BNCT effectiveness will come from improved boron delivery agents, improved boron administration protocols, or through combination of BNCT with other modalites.

BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states.

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 Abstract

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 (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, 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” (Na2B12H11SH). 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., National Institutes of Health (U.S.), United States. Dept. of Energy

Introduction of a bis(isopropylidene)-protected galactopyranosyl moiety in s-triazine-based boron-rich carboxylic acids and amines results in soluble and suitable coupling partners for tumour-selective biomolecules with applications as selective agents for boron neutron capture therapy (BNCT). Bearing either a carboxylic acid or primary amine as a functional group, these compounds are highly versatile and thus largely extend the possible coupling strategies with suitable biomolecules. Modification of the gastrin-releasing peptide receptor (GRPR) selective agonist [D-Phe6, β-Ala11, Ala13, Nle14]Bn(6–14) with the carboxylic acid derivative yielded a bioconjugate with an optimal receptor activation and internalisation profile. This demonstrates the great potential of this approach for the development of novel boron delivery agents.

Boron neutron capture therapy (BNCT) is a targeted therapy, which consists of preferential accumulation of boron carriers in tumor followed by neutron irradiation. Each oral cancer patient has different risks of developing one or more carcinomas and/or oral mucositis induced after treatment. Our group proposed the hamster oral cancer model to study the efficacy of BNCT and associated mucositis. Translational studies are essential to the advancement of novel boron delivery agents and targeted strategies. Herein, we review our work in the hamster model in which we studied BNCT induced mucositis using three different cancerization protocols, mimicking three different clinical scenarios. The BNCT-induced mucositis increases with the aggressiveness of the carcinogenesis protocol employed, suggesting that the study of different oral cancer patient scenarios would help to develop personalized therapies.

Carbon-bearing boron hydrides, also known as carboranes, are polyhedral clusters composed of hydrogen, boron, and carbon and are closely related to boranes. Because of their esthetically pleasing symmetry as well as unusual chemical properties, carboranes have attracted immense interest. Studies over the past 40 years have revealed them to have chemical features that make them useful in a number of specialized applications such as conducting organic polymers, nuclear waste remediation, and as liquid crystalline materials. It has also been shown that carboranes can be used as boron delivery agents for boron neutron capture therapy against cancer. While a number of strides have been made in synthesizing these molecules, their characterization by NMR spectroscopy is challenging due to boron–boron and boron–hydrogen coupling. This gives rise to broad and unresolved peaks and makes peak assignment difficult and often based on best guesses. NMR structural characterization studies of carborane compounds are sparse, dated, and often performed at low resolution. This report provides a detailed structural characterization of an m-carborane derivative, featuring high-resolution multi-dimensional NMR spectroscopy (2-D 1H–1H, 2-D 11B–11B, 2-D 11B–1H, and 2-D 13C–1H). The asymmetry of the carborane cluster (a consequence of substitution at one of the two cluster carbons) adds a dimension of complexity to the spectra, whose peaks could be assigned nevertheless due to their high resolution.

The radiation dose delivered to cells in vitro or in vivo during boron neutron capture therapy (BNCT) is a mixture of photons, fast neutrons and heavy charged particles from the interaction of neutrons with nitrogen and boron. The concept of relative biological effectiveness (RBE) has been developed to allow comparison of the effects of these radiations with the effects of standard photon treatments such as 250 kVp x-rays or 60Co gamma rays. The RBE value for all of these high linear energy transfer radiations can vary considerably depending upon the experimental conditions and endpoint utilized (c.f. Fukuda, 1989). The short range of the particles from the 10B(n,α)7Li reaction make the precise subcellular location of the 10B atom of critical importance. The microscopic distribution of the 10B has a decided effect on the dosimetry. Monte Carlo simulations have shown that, at the cellular level, there is a profound difference in the probability of cell kill depending on the location of the 10B relative to the nucleus (Gabel, 1987). Convenient analytical techniques for the detection of boron at the cellular and subcellular level remain to be developed. Different boron-delivery agents will almost certainly have different distribution patterns at the subcellular level. For equivalent 10B concentrations at the macroscopic level (e.g. µg 10B/gram wet tissue), different boron-delivery agents may have vastly different cytotoxic effects. The application of a single RBE value for the 10B(n,α)7Li reaction to different boron-delivery agents without some experimentally determined compensatory factor for subcellular localization could lead to gross under- (or over-) estimates of the actual absorbed dose.

Boron Neutron Capture Therapy (BNCT) is based on boron-10 neutron capture, producing an alpha particle and a lithium-7 nucleus. Tumoral cells are targeted by boron delivery agents. Neutron field irradiation of the tumor generate alpha particles and Li-7 inside the targeted cells. This cellular selectivity enables the use of this radiotherapy for recurrent and metastasized cancers, in which tumor tissue spread in normal tissue. BNCT have been used in clinical trails as a treatment for recurrent brain, head and neck cancers. However, the need for a sustainable neutron source in a hospital environment leads to the transition of reactor-based BNCT to accelerator-based BNCT, using compact accelerators of proton and deuteron beams coupled to solid or liquid targets. New characterizations of the neutron field are needed at the target level and after moderation.This manuscript details new elements to define an adapted neutron source for non-superficial tumors. Those elements are used in a moderator's numerical design, and an original method is described to validate the neutron source experimentally before clinical use. A numerical study based on Monte-Carlo methods was used to demonstrate the interest in reducing the neutron energy usually considered as adapted to treat deep-seated tumors of 10 keV to 1 keV. This diminution increases the contrast between the dose in the tumor and healthy tissues for tumors seated up to 6 cm depth. These results were used for the design of an original moderator. Simulations were realized to determine the adapted parameters to treat tumors located beyond 3 cm depth. Studies prescribe the use of a heavy water moderator, with a 25 cm radius for the half-sphere composing the moderator in order to improve the ratio between tumor dose and normal tissues dose. This moderator design extends treatment possibilities, with the possible irradiation of more than one patient by the same neutron source. This thesis also introduces a new method to experimentally validate the neutron source characteristics (from a dosimetric point of view) with a proof of concept of using a MIMAC micro-TPC detector as an active fantom. This use of the detector is characterized by measuring the therapeutic dose inside a reference material, at an equivalent depth of a given tumor depth inside tissues. This dose measurement is done by counting the number of neutron captures on a 10B sample. The use of that type of detector allows to discriminate and correctly characterize neutron capture on 10B of the sample. Moreover, the configuration used during the experiment is adapted to spectrometry in the epithermal range. This experiment demonstrates the possibility of using one detector to characterize spectroscopically and dosimetrically neutron fields in BNCT.This thesis's work could be completed by a more detailed study on the influence of local dose distribution in the moderator's conception. The experimental method presented needs validation of the double use of the MIMAC micro-TPC detector using a reference epithermal neutron field., La Radiothérapie par Capture Neutronique du Bore (acronyme BNCT en anglais) repose sur l’utilisation de la capture neutronique sur l’isotope 10B du bore. Son principe se fonde sur la combinaison d’une fixation du 10B sur les cellules tumorales et d’une irradiation de neutrons épithermiques (E < 10 keV) entraînant l’irradiation de la cellule ciblée par des alphas et Li-7, produits de la réaction nucléaire. En raison de sa sélectivité à l’échelle cellulaire, cette radiothérapie apporte une solution de traitement pour les cancers récurrents ou métastasés dont les tissus tumoraux se mêlent aux tissus sains.La BNCT été utilisée dans des essais cliniques pour le traitement de cancers récurrents du cerveau, de la tête et du cou. Cependant, la nécessité d’une source neutronique viable en environnement hospitalier a engagé le passage de l'utilisation d'un réacteur nucléaire à des sources utilisant des accélérateurs compacts de protons ou deutonss. Cette transition s’accompagne d’un besoin de caractériser le champ neutronique au niveau de la cible et après modération.Ce manuscrit présente de nouveaux éléments de définition de cette source neutronique, utilisés pour la conception numérique d’un modérateur ainsi que la méthode permettant de valider expérimentalement la source neutronique avant son utilisation pour un traitement. Une étude par simulation numérique de méthode de Monte-Carlo a permi de démontrer l’intérêt de la diminution de 10 keV à 1 keV de l’énergie épithermique limite du champ neutronique source. Pour des tumeurs situées jusqu’à environ 6 cm de profondeur dans le cerveau, cette diminution permet d’améliorer le contraste entre la dose reçue par les tissus sains et les tissus tumoraux. Ces résultats ont été utilisé pour la conception d’un modérateur innovant. Des simulations ont été réalisées pour déterminer les paramètres adaptés au traitement de tumeurs situées à plus de 3 cm dans les tissus. Les recherches effectuées préconisent l’utilisation de l’eau lourde et d’un rayon de 25 cm pour la demi-sphère caractéristique du modérateur afin d’améliorer le rapport entre la dose dans les tissus sains et dans la tumeur. Le modèle de ce modérateur permet l’ouverture du traitement à l’irradiation de plusieurs patients par la même source neutronique. Cette thèse présente aussi une méthode de validation expérimentale de la source neutronique sous forme d’une preuve de concept de l’utilisation d’un détecteur micro-TPC type MIMAC en tant que fantôme actif. Cette utilisation du détecteur se caractérise par la mesure de la dose thérapeutique dans un matériau de référence à une profondeur équivalente à une profondeur donnée de tumeur dans les tissus. Cette mesure de dose est effectuée par comptage du nombre de captures neutroniques sur un échantillon de 10B. L’utilisation de ce type de détecteur permet de discriminer et de correctement caractériser la production d’une capture. De plus, la configuration utilisée lors de l’expérience est adaptée à la spectrométrie dans le domaine épithermique. Cette expérience démontre la possibilité de l’utilisation d’un seul détecteur pour caractériser de manière dosimétrique et spectroscopique le champ neutronique en BNCT.L’ensemble du travail de cette thèse pourra être complété par une étude plus approfondie de l’influence de la répartition locale de la dose dans la conception du modérateur. La méthode expérimentale exposée appelle à une validation de l’utilisation double du détecteur micro-TPC type MIMAC dans un champ neutronique épithermique de référence.

Nowadays, Cancer is undoubtedly a consequential and potentially life-threatening illness. In the U.S., Around 1.7 million people discerned with Cancer last year. The application of boron in cancer treatment is applicable as therapy known as Boron Neutron Capture Therapy (BNCT). It is an analeptic technique that depends on the nuclear capture and fission reaction that results in various particles such as Li, He nuclei with their kinetic energy and γ-radiation. These radiations kill the malignant cells in our body without damaging the normal tissue. Boron particles delivered selectively to only malignant cells by minimizing their concentration in normal cells. In this article, The clinical trials, clinical investigation in Different countries with a different type of Cancer as Lung, Brain, Head/Neck, Hepatic and gastrointestinal. Various delivery methods of Boron agents in the tumor cells recently developed boron delivery agents, and different techniques of their dose distribution explain. In recent years, boron compounds were applied with porphyrin, copolymers, nanoparticles, other peptides, EGRF’s, and Liposomes to intensify their killer properties toward target cancer cells. BNCT is also effectively used for the medication of various kinds of Cancers explained. The purpose of this article is to indicate the intelligible way of BNCT(Reactor-Based) for the treatment of malignant cells.

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.

Boron neutron capture therapy (BNCT) allows the selective elimination of malignant tumor cells without affecting healthy tissue. Although this binary radiotherapy approach has been known for decades, BNCT failed to reach the daily clinics to date. One of the reasons is the lack of selective boron delivery agents. Using boron loaded peptide conjugates, which address G protein-coupled receptors overexpressed on tumor cells allow the intracellular accumulation of boron. The gastrin-releasing peptide receptor (GRPR) is a well-known target in cancer diagnosis and can potentially be used for BNCT. Here, we present the successful introduction of multiple bis-deoxygalactosyl-carborane building blocks to the GRPR-selective ligand [d-Phe

Boron neutron capture therapy (BNCT) is a binary cancer therapy, which combines the biochemical targeting of a boron-containing drug with the regional localization of radiation treatment. Although the concept of BNCT has been known for decades, the selective delivery of boron into tumor cells remains challenging. G protein-coupled receptors that are overexpressed on cancer cells in combination with peptidic ligands can be potentially used as shuttle system for a tumor-directed boron uptake. In this study, we present the generation of short, boron-rich peptide conjugates that target the ghrelin receptor. Expression of the ghrelin receptor on various cancer cells makes it a viable target for BNCT. We designed a novel hexapeptide super-agonist that was modified with different specifically synthesized carborane monoclusters and tested for ghrelin receptor activation. A meta-carborane building block with a mercaptoacetic acid linker was found to be optimal for peptide modification, owing to its chemical stability and a suitable activation efficacy of the conjugate. The versatility of this carborane for the development of peptidic boron delivery agents was further demonstrated by the generation of highly potent, boron-loaded conjugates using the backbone of the known ghrelin receptor ligands growth hormone releasing peptide 6 and Ipamorelin.

Boron neutron capture therapy (BNCT) is a binary therapeutic 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 and recoiling lithium-7 nuclei. In this Commentary we will focus on a number of papers that were presented at a Symposium entitled “Current Clinical Status of Boron Neutron Capture Therapy and Paths to the Future”, which was held in September 2017 at the China National Convention Center in Beijing. Results were presented by clinicians from Japan, Finland, the United States, the China mainland and Taiwan, China who have been working in the multiple disciplines that are required for carrying out clinical BNCT. The main focus was on the treatment of patients with malignant brain tumors, recurrent tumors of the head and neck region, and cutaneous melanomas. The results obtained in treating these patients were reported in detail and, although most of the patients with brain tumors and head and neck cancer were not cured, there was evidence of some clinical efficacy. Although there are a number of problems that must be addressed, further clinical studies to evaluate the efficacy of BNCT are warranted. First, despite considerable effort by numerous investigators over the past 40 years, there still are only two boron-containing drugs in clinical use, l-boronophenylalanine (BPA) and sodium borocaptate (BSH). Therefore, until new and more effective boron delivery agents are developed, efforts should be directed to improving the dosing and delivery of BPA and BSH. Second, due to a variety of reasons, nuclear reactor-based BNCT has ended except for its use in the China mainland and Taiwan. Therefore, the future of BNCT depends upon the results of the ongoing Phase II clinical trials that are being carried out in Japan and the soon to be initiated trials that will be carried out in Finland. If the results obtained from these clinical trials are sufficiently promising, then BNCT will have a clear path to the future, especially for patients with the therapeutically challenging malignancies that in the past have been treated with reactor-based BNCT.

A series of seven BODIPYs functionalized with ortho-carborane groups at the 8(meso) or 3/5(α) position were synthesized and characterized by NMR, HRMS, HPLC, and in the cases of 2b and 5b, by X-ray analysis. The BODIPYs exhibited low dark toxicity and phototoxicity toward human glioma T98G cells, and their cellular uptake varied significantly, with 5b accumulating the most and 7 the least. All BODIPYs localized mainly within the cell ER. The BODIPYs showed higher permeabilities than lucifer yellow across human hCMEC/D3 brain endothelial cell monolayers as the BBB model. Among this series, 1b showed the highest BBB permeability (Pe = 16.4 × 10(-5) cm/s), probably as a result of its lower MW (366 Da) and favorable hydrophobicity (log P = 1.5). The combination of low cytotoxicity, amphiphilicity, high boron content, high cellular uptake, and moderate BBB permeability renders these compounds promising boron delivery agents for the BNCT of brain tumors.

Boron-neutron capture therapy (BNCT) is an attractive technique for cancer treatment. As such, α, α-cycloalkyl amino acids containing thiododecaborate ([B12H11](2-)-S-) units were designed and synthesized as novel boron delivery agents for BNCT. In the present study, new thiododecaborate α, α-cycloalkyl amino acids were synthesized, and biological evaluation of the boron compounds as boron carrier for BNCT was carried out.

Seven polyamine conjugates of a tri(p-carboranylmethylthio)tetrafluorophenylporphyrin were prepared in high yields by sequential substitution of the p-phenyl fluoride of tetrakis(pentafluorophenyl)porphyrin (TPPF), and investigated as boron delivery agents for boron neutron capture therapy (BNCT). The polyamines used were derivatives of the natural-occurring spermine with different lengths of the carbon chains, terminal primary amine groups and, in two of the conjugates, additional aminoethyl moieties. A tri(polyethylene glycol) conjugate was also synthesized for comparison purposes. The polyamine conjugates showed low dark cytotoxicity (IC(50) >400 μM) and low phototoxicity (IC(50) >40 μM at 1.5 J/cm(2)). All polyamine conjugates, with one exception, showed higher uptake into human glioma T98G cells (up to 12-fold) than the PEG conjugate, and localized preferentially in the cell ER, Golgi and the lysosomes. Our results show that spermine derivatives can serve as effective carriers of boronated porphyrins for the BNCT of tumors.

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce α-particles (10B[n,α]7Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these have been evaluated in the present study: 5,10,15,20-tetra-(4-nido-carboranyphenyl)tetrabenzoporphyrin (H2TBP), 5,10,15,20-tetra-(4-nido-carboranylphenyl)porphyrin (H2TCP) and 5,15-di-[3,5-(nido-carboranylmethyl)phenyl]-porphyrin (H2DCP). The goals of this study were two-fold. First, to determine the biodistribution of H2TBP, H2TCP and H2DCP following intracerebral (i.c.) administration by means of short term (30 min) convection enhanced delivery (CED) or sustained delivery over 24 h by osmotic pumps to F98 glioma bearing rats. Second, to determine the efficacy of H2TCP and H2TBP as boron delivery agents for BNCT in F98 glioma bearing rats. Tumor boron concentrations immediately after i.c. osmotic pump delivery were high (36–88 µg/g) and they remained so at 24 h (62–103 µg/g) The corresponding normal brain concentrations were low (0.8–5.2 µg/g) and the blood and liver concentrations were all undetectable. Based on these data, therapy studies were initiated at the Massachusetts Institute of Technology (MIT) Research Reactor (MITRR) with H2TCP and H2TBP 24 h after CED or osmotic pump delivery. Mean survival times (MST) of untreated and irradiated control rats were 23±3 and 27±3 d, respectively, while animals that received H2TCP or H2TBP, followed by BNCT, had a MST of 35±4 d and 44±10 d, respectively, which were better than those obtained following i.v. administration of boronophenylalanine (37±3 d). However, since the tumor boron concentrations of the carboranylporphyrins were 3–5X > i.v. BPA (~25 µg/g), we had expected that the MSTs would have been greater. Histopathologic examination of brains of BNCT treated rats revealed that there were large numbers of porphyrin-laden macrophages, as well as extracellular accumulations of porphyrins indicating that the seemingly high tumor boron concentrations did not represent the true tumor cellular uptake. Our data are the first to show that carboranyl porphyrins are effective delivery agents for BNCT of an experimental brain tumor. Based on these results, we now are in the process of evaluating carboranylporphyrins that could have enhanced cellular uptake following administration and improved therapeutic efficacy.

There is a pressing need for new and more efficient boron delivery agents to tumor cells for use in boron neutron capture therapy (BNCT). A class of boronated unnatural cyclic amino acids has demonstrated a remarkable selectivity toward tumors in animal and cell culture models, far superior to currently used agents in clinical BNCT. One of these amino acids, 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC), has shown a tumor to blood ratio of 8 and a tumor to normal brain ratio of nearly 21 in a melanoma bearing mouse model. This work represents further biological characterization of this compound for tumor targeting in an EMT6 murine mammary carcinoma mouse model and a T98G human glioblastoma cell line. Female BALB/c mice bearing EMT6 tumors were injected with the fructose complex form of racemic mixtures of cis- and trans isomers of ABCPC in identical concentrations. Boron concentrations were measured in the tumor, blood, brain, skin, and liver tissues at 1, 3, and 5 hr post injection. These observations revealed a remarkable difference in racemic mixtures of cis and trans isomers in tumor targeting by boron. This implies that further separation of the L and D forms of this compound may enhance tumor targeting to an even higher degree than that provided by the racemic mixtures. Since the uptake measurements were made in homogenized tumor and normal tissues, little is known about the subcellular location of the boron arising from the various isomeric forms of the amino acid. To study subcellular delivery of boron from ABCPC in T98G human glioblastoma cells, we employed secondary ion mass spectrometry (SIMS) based technique of ion microscopy, which is capable of quantitatively imaging isotopic (elemental) gradients in cells and tissues at 500 nm spatial resolution. The T98G cells were exposed to the nutrient medium containing 100 ppm boron equivalent of a mixture of both L and D isomers of ABCPC in the form of a fructose complex for 1 hr. Following this treatment, the cells were fast frozen, freeze-fractured, and freeze-dried for SIMS analysis. Within an hour of exposure, ABCPC provided partitioning of intracellular to extracellular boron of 3/1. SIMS imaging revealed that boron from ABCPC was distributed throughout the cell, including the nucleus. This level of boron delivery within an hour of exposure is superior to p-boronophenylalanine (BPA) and sodium borocaptate (BSH), which have been previously studied by SIMS in the same cell line. These encouraging observations provide compelling support for further isomeric separations of ABCPC into the D and L forms for enhanced tumor targeting and continued testing of these compounds as new boron carriers in BNCT.

An account of the current research carried out in our laboratories is presented. Included is the incorporation of several group 14 elements into charge-compensated carboranes. These species present a bonding pattern not found in other main group carboranes. In addition to our continuing studies of the syntheses and structures of organometallic compounds, the use of these compounds as catalysts and catalyst precursors has been investigated. The isotopic exchange reactions between 10B enriched boron hydrides with naturally abundant boranes catalyzed by Ru(0) nanoparticles has been studied. The Ru(0) nanoparticles were obtained by the reduction of [CpRuCp∗RuCp∗]PF6 (Cp∗ = C5Me5) with hydrogen and stabilized by the ionic liquid trihexyltetradecylphosphonium dodecylbenzenesulfonate [THTdP][DBS]. This was found to be an excellent, long lived catalyst for the exchange reaction of B-10 enriched diborane and naturally abundant decaborane(14). Other approaches to the production and use of nano-metal catalysts have also been explored. The reduction of the iridium carborane, (PPh3)2IrH(7,8-C2B9H11) with hydrogen in the presence of trihexyltetradecylphosphonium methylsulfonate, [THTdP][MS], produced an Ir(0) nanoparticles that catalyzed the phenylborolation as did our Ir(sal = N-R = salicylaldiminato; COD = cyclooctadiene complex. Progress in the use of single wall carbon nanotubes (SWCNT) as boron delivery agents was also discussed.

In this article we report the physicochemical characterization of cationic liposomes loaded with orthocarborane and two of its sugar-containing derivatives. Carboranes are efficient boron delivery agents in boron neutron capture therapy, an anti-cancer treatment based on neutron absorption by 10B nuclei. Cationic liposomes were prepared using the positively charged DOTAP and the zwitterionic DOPE, as a helper lipid. These liposomes are currently used in gene therapy for their ability in targeting the cell nucleus; therefore they can be considered appropriate vectors for boron neutron capture therapy, in the quest of reducing the high boron amount that is necessary for successful cancer treatment. Boron uptake was determined by an original in situ method, based on neutron absorption. The structural properties of the loaded liposomes were studied in detail by the combined use of small angle x-ray scattering and small angle neutron scattering. These techniques established the global shape and size of liposomes and their bilayer composition. The results were discussed in term of molecular properties of the hosted drugs. Differences found in the insertion modality were correlated with the preparation procedure or with the specific shape and lipophilic-hydrophilic balance of each carborane.

The purpose of the present study was to evaluate both in vitro and in vivo a series of boron-containing nucleosides that potentially could be used as delivery agents for neutron capture therapy. The rationale for their synthesis was based on the fact that proliferating neoplastic cells have increased requirements for nucleic acid precursors, and, therefore, they should preferentially localize in the tumor. A series of 3-carboranlyalkyl thymidine analogs has been synthesized and a subset, designated N4, N5, and N7, and the corresponding 3-dihydroxypropyl derivatives, designated N4–2OH, N5–2OH, and N7–2OH, have been selected for evaluation. Using these compounds as substrates for recombinant human thymidine kinase-1 and the mitochondrial isoenzyme thymidine kinase-2, the highest phosphorylation levels relative to thymidine were seen with N5 and the corresponding dihydroxypropyl analog N5–2OH. In contrast, N4, N4-OH, N7, and N7-OH had substantially lower phosphorylation levels. To compare compounds with high and low thymidine kinase-1 substrate activity, N5 and N7 and the corresponding dihydroxypropyl derivatives were selected for evaluation of their cellular toxicity, uptake and retention by the F98 rat glioma, human MRA melanoma, and murine L929 cell lines, all of which are thymidine kinase-1(+), and a mutant L929 cell line that is thymidine kinase-1(−). N5–2OH was the least toxic (IC50, 43–70 μm), and N7 and N7–2OH were the most toxic (IC50, 18–49 μm). The highest boron uptake was seen with N7–2OH by the MRA 27 melanoma and L929 wild-type (wt) cell lines. The highest retention was seen with L929 (wt) cells, and this ranged from 29% for N5–2OH to 46% for N7. Based on the in vitro toxicity and uptake data, N5–2OH was selected for in vivo biodistribution studies either in rats bearing intracerebral implants of the F98 glioma or in mice bearing either s.c. or intracerebral implants of L929 (wt) tumors. At 2.5 hours after convection-enhanced delivery, the boron values for the F98 glioma and normal brain were 16.2 ± 2.3 and 2.2 μg/g, respectively, and the tumor to brain ratio was 8.5. Boron values at 4 hours after convection-enhanced delivery of N5–2OH to mice bearing intracerebral implants of L929 (wt) or L929 thymidine kinase-1(−) tumors were 39.8 ± 10.8 and 12.4 ± 1.6 μg/g, respectively, and the corresponding normal brain values were 4.4 and 1.6 μg/g, thereby indicating that there was selective retention by the thymidine kinase-1(+) tumors. Based on these favorable in vitro and in vivo data, neutron capture therapy studies will be initiated using N5–2OH in combination with two non-cell cycle dependent boron delivery agents, boronophenylalanine and sodium borocaptate.