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

Abstract 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]

This proceeding article compiles current research on the development of boron delivery drugs for boron neutron capture therapy that was presented and discussed at the National Cancer Institute (NCI) Workshop on Neutron Capture Therapy that took place on April 20-22, 2022. The most used boron sources are icosahedral boron clusters attached to peptides, proteins (such as albumin), porphyrin derivatives, dendrimers, polymers, and nanoparticles, or encapsulated into liposomes. These boron clusters and/or carriers can be labeled with contrast agents allowing for the use of imaging techniques, such as PET, SPECT, and fluorescence, that enable quantification of tumor-localized boron and their use as theranostic agents.

G-protein-coupled receptors like the human Y 1 receptor (hY 1 R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY 1 R-preferring ligand [F 7 ,P 34 ]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY 1 R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.

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 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 an advanced radiation therapy technique that is rapidly developing in the field of cancer treatment. This technique, an atomic-level binary targeted therapy, kills cancer cells by causing a 10B(n, α)7Li nuclear reaction within the cancer cells, and its clinical implementation requires professional technology and device support. The core elements of BNCT include appropriate neutron sources and neutron capture drugs. Compared with traditional radiotherapy techniques, BNCT shows outstanding advantages in treating locally recurrent tumors, such as central nervous system tumors and head and neck tumors. Furthermore, it can better protect normal organs, especially for tumors that have already significantly invaded surrounding organs, demonstrating its promising future prospects. This article mainly elaborates on the technical principles, core elements, and clinical applications of BNCT, in hope of providing reference for clinical diagnosis and treatment.

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.

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.

The purpose of the present study was to evaluate 2' and 5'-O-(o-carboran-1-ylmethyl)uridine (CBU-2' and CBU-5') as delivery agents for Boron Neutron Capture Therapy (BNCT) of brain tumors. The in vitro cellular uptake, persistence, subcellular distribution and cytotoxicity, and in vivo biodistribution of CBU-2' have been studied as follows. Cellular uptake studies were carried out with the F98 rat glioma, U-87 MG human glioma, B16 melanoma, SP2/0 myeloma and MDCK fibroblasts. All tumor and non-tumor cell lines had high uptake of CBU-2' (46-75 ppm), indicating that uptake was not selective for neoplastic cells and was independent of cell proliferation. In vitro persistence studies showed high cellular retention of CBU-2' compared to sodium borocaptate (BSH), when cells were transferred from boron-containing to boron-free medium and cultured for an additional 24-48 hours. Subcellular fractionation revealed 75.6% of the recoverable boron was cell membrane associated, 15.6% was in the cytosol, and 8.8% was in the nuclear fraction, but no boron was detectable in the RNA and DNA fractions. F98 glioma cells were cultured in the presence of 3 metabolic inhibitors (rotenone, dipyridamole and NBMPR ¿6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine¿) and none of these blocked the cellular uptake of CBU-2' suggesting that uptake was neither energy nor nucleoside transport dependent. In vivo studies in F98 glioma bearing rats showed that CBU-2' in tumor attained concentrations of 8.0 +/- 2.1 micrograms B/g tissue, which was 13 x greater than that in normal brain of the ipsilateral and contralateral cerebral hemispheres (0.6 +/- 0.2 microgram B/g). The B levels, however, were still lower than the minimum 20-35 microgram B/g, which are required for in vivo BNCT. In summary, our in vitro and in vivo data indicate that CBU-2' was not sufficiently selective for in vivo targeting of brain tumors. However, CBU-2' and CBU-5' were highly toxic for F98 glioma cells in vitro (IC50 = 3 - 13 x 10(-5) M), as determined by measuring the uptake of 3H-thymidine, and the survival of F98 glioma cells using a clonogenic assay, which suggests that these compounds should be further evaluated as potential cytoreductive chemotherapeutic agents.

Boron neutron capture therapy (BNCT) is an emerging approach for treating malignant tumors with binary targeting. However, its clinical application has been hampered by insufficient 10B accumulation in tumors and low 10B concentration ratios of tumor-to-blood (T/B) and tumor-to-normal tissue (T/N). Herein, we developed fluorinated BPA derivatives with different fluorine groups as boron delivery agents for enabling sufficient 10B accumulation in tumors and enhancing T/B and T/N ratios. Our findings demonstrated that fluorinated BPA derivatives had good biological safety. Furthermore, fluorinated BPA derivatives showed improved 10B accumulation in tumors and enhanced T/B and T/N ratios compared to the clinical boron drug fructose-BPA (f-BPA). In particular, in B16-F10 tumor-bearing mice, fluorinated BPA derivatives met the requirements for clinical BNCT even at half of the clinical dose. Thus, fluorinated BPA derivatives are potentially effective boron delivery agents for clinical BNCT in melanoma. [ABSTRACT FROM AUTHOR]