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2024 DEC 14 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on Cancer have been presented. According to news reporting from [...]

A recent study conducted at the University of Eastern Finland explored the potential of boronated tryptophans as boron delivery agents for Boron Neutron Capture Therapy (BNCT) in cancer treatment. The researchers synthesized both enantiomers of 5- and 6-boronotryptophans and evaluated their uptake in human cancer cell lines, finding differences in boron compound accumulation between the cell lines. The study suggests that tryptophan derivatives could be effective boron carriers in cases where the clinically used boron carrier, l-BPA, is ineffective. The research has been peer-reviewed and offers valuable insights into potential advancements in cancer therapy. [Extracted from the article]

2020 MAR 28 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A new study on Cancer is now available. According to news reporting [...]

G-protein-coupled receptors like the human Y1receptor (hY1R) 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 hY1R-preferring ligand [F7,P34]-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 hY1R-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.

For more information on this research see: Multi-Functional Boron-Delivery Agents for Boron Neutron Capture Therapy of Cancers. Keywords: Biotechnology; Boron Neutron Capture Therapy; Cancer; Cancer Gene Therapy; Clinical Research; Clinical Trials and Studies; Drugs and Therapies; Emerging Technologies; Gene Therapy; Health and Medicine; High-Energy Radiotherapy; Nanoparticles; Nanotechnology; Neutron Capture Therapy; Oncology; Pharmaceuticals; Post-Trial Research; Radiotherapy; Therapy EN Biotechnology Boron Neutron Capture Therapy Cancer Cancer Gene Therapy Clinical Research Clinical Trials and Studies Drugs and Therapies Emerging Technologies Gene Therapy Health and Medicine High-Energy Radiotherapy Nanoparticles Nanotechnology Neutron Capture Therapy Oncology Pharmaceuticals Post-Trial Research Radiotherapy Therapy 19 19 1 07/10/23 20230710 NES 230710 2023 JUL 10 (NewsRx) -- By a News Reporter-Staff News Editor at Cancer Gene Therapy Week -- Researchers detail new data in cancer gene therapy. [Extracted from the article]

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 (10B) 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.

Researchers at Taiyuan University of Technology in China have developed a new strategy for cancer treatment called boron neutron capture therapy (BNCT). BNCT combines targeted particle radiotherapy with chemodynamic therapy-enhanced ferroptosis. The researchers designed redox-responsive boron nano-chains (RBNC) that release boron delivery agents in response to the tumor microenvironment, resulting in high boron accumulation at the tumor site. This approach addresses the challenges of achieving adequate boron concentration in deep-seated tumors and poor targeting of boron delivery agents. The study provides a potential solution for improving the effectiveness of BNCT combined with chemodynamic therapy and ferroptosis. [Extracted from the article]

A recent study conducted by researchers from the University of Helsinki explores the development of carbohydrate delivery agents for Boron Neutron Capture Therapy (BNCT), a cancer treatment that combines boron delivery agents with thermal neutrons to selectively target and eliminate cancer cells. The researchers synthesized and evaluated a set of fluorinated carbohydrate derivatives and found that they may have advantages over current boron delivery agents in terms of improved boron delivery capacity at the cellular level. However, the carbohydrate delivery agents also exhibited strong binding to plasma proteins, which may require further investigation before progressing to in vivo studies. This research provides valuable insights for the future development of theranostic agents for BNCT based on carbohydrates. [Extracted from the article]

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

A recent study conducted at Nanjing University in China has developed a new type of boron delivery agent for boron neutron capture therapy (BNCT) in cancer treatment. The agent combines aggregation-induced emission (AIE)-active imaging, a carborane cluster, and an erlotinib targeting unit for lung cancer cells. The boron delivery agents demonstrated excellent imaging properties and selective accumulation in tumors, resulting in highly efficient tumor growth suppression without observable tissue damage. This study expands the application of AIE-active molecules and boron clusters and provides a new molecular engineering strategy for cancer therapy based on BNCT. [Extracted from the article]

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 vitroassessment thereby pointing toward the significant potential embedded in this approach.

This review provides an essential overview on the progress of rapidly-developing China’s radiopharmaceuticals in recent years (2014–2021). Our discussion reflects on efforts to develop potential, preclinical, and in-clinical radiopharmaceuticals including the following areas: (1) brain imaging agents, (2) cardiovascular imaging agents, (3) infection and inflammation imaging agents, (4) tumor radiopharmaceuticals, and (5) boron delivery agents (a class of radiopharmaceutical prodrug) for neutron capture therapy. Especially, the progress in basic research, including new radiolabeling methodology, is highlighted from a standpoint of radiopharmaceutical chemistry. Meanwhile, we briefly reflect on the recent major events related to radiopharmaceuticals along with the distribution of major R&D forces (universities, institutions, facilities, and companies), clinical study status, and national regulatory supports. We conclude with a brief commentary on remaining limitations and emerging opportunities for China’s radiopharmaceuticals.

Lanzhou, People's Republic of China, Asia, Boron Neutron Capture Therapy, Cancer, Gastroenterology, Health and Medicine, High-Energy Radiotherapy, Oncology, Pancreas, Pancreatic Cancer, Pancreatic Neoplasms, Radiotherapy, Neutron Capture Therapy Keywords: Lanzhou; People's Republic of China; Asia; Boron Neutron Capture Therapy; Cancer; Gastroenterology; Health and Medicine; High-Energy Radiotherapy; Neutron Capture Therapy; Oncology; Pancreas; Pancreatic Cancer; Pancreatic Neoplasms; Radiotherapy EN Lanzhou People's Republic of China Asia Boron Neutron Capture Therapy Cancer Gastroenterology Health and Medicine High-Energy Radiotherapy Neutron Capture Therapy Oncology Pancreas Pancreatic Cancer Pancreatic Neoplasms Radiotherapy 1061 1061 1 04/10/23 20230414 NES 230414 2023 APR 11 (NewsRx) -- By a News Reporter-Staff News Editor at Drug Week -- Investigators discuss new findings in Oncology - Pancreatic Cancer. Keywords for this news article include: Lanzhou, People's Republic of China, Asia, Boron Neutron Capture Therapy, Cancer, Gastroenterology, Health and Medicine, High-Energy Radiotherapy, Neutron Capture Therapy, Oncology, Pancreas, Pancreatic Cancer, Pancreatic Neoplasms, Radiotherapy, Lanzhou University. [Extracted from the article]

Keywords: Boron Neutron Capture Therapy; Cancer; Gastroenterology; Health and Medicine; High-Energy Radiotherapy; Neutron Capture Therapy; Oncology; Pancreas; Pancreatic Cancer; Pancreatic Neoplasms; Radiotherapy EN Boron Neutron Capture Therapy Cancer Gastroenterology Health and Medicine High-Energy Radiotherapy Neutron Capture Therapy Oncology Pancreas Pancreatic Cancer Pancreatic Neoplasms Radiotherapy 788 788 1 03/24/23 20230228 NES 230228 2023 FEB 28 (NewsRx) -- By a News Reporter-Staff News Editor at Cancer Weekly -- Data detailed on pancreatic cancer have been presented. Boron Neutron Capture Therapy, Cancer, Gastroenterology, Health and Medicine, High-Energy Radiotherapy, Oncology, Pancreas, Pancreatic Cancer, Pancreatic Neoplasms, Radiotherapy, Neutron Capture Therapy. [Extracted from the article]

Boron neutron capture therapy (BNCT) is a cancer therapy in which boron delivery agents play a crucial role. In theory, delivery agents with high tumor targeting capabilities can lead to selective eradication of tumor cells without causing harmful side effects. We have been working on a GLUT1-targeting strategy to BNCT for a number of years and found multiple promising hit compounds which outperform the clinically employed boron delivery agents in vitro. Herein, we continue our work in the field by further diversification of the carbohydrate scaffold in order to map the optimal stereochemistry of the carbohydrate core. In the sweet battle of the epimers, carborane-bearing d-galactose, d-mannose, and d-allose are synthesized and subjected to in vitro profiling studies─with earlier work on d-glucose serving as the reference. We find that all of the monosaccharide delivery agents display a significantly improved boron delivery capacity over the delivery agents approved for clinical use in vitro, thus providing a sound foundation for advancing toward in vivo preclinical assessment studies.

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-Phe6, β-Ala11, Ala13, Nle14]Bn(6–14) (sBB2L) generating peptide conjugates with up to 80 boron atoms per molecule. Receptor activation was retained, metabolic stability was increased, and uptake into PC3 cells was proven without showing any intrinsic cytotoxicity. Furthermore, undesired uptake into liver cells was suppressed by using l-deoxygalactosyl modified carborane building blocks. Due to its high boron loading and excellent GRPR selectivity, this conjugate can be considered as a promising boron delivery agent for BNCT.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with10B 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.

A new group of charge-compensated nido-carboranyl derivatives of sulfur-containing amino acids and biotin has been synthesized in which the boron atom in position 9 or 10 of carborane is attached to a positively charged sulfur atom. The possibilities of obtaining symmetrical B(10)-substituted and asymmetric B(9)-substituted nido-carboranes were studied. Using the example of (S)-methionine and D-biotin derivatives, water-soluble S-substituted charge-compensated nido-carboranes with free functional groups were prepared. The results obtained open up prospects for the development of potential boron delivery agents for BNCT as well as new bioactive compounds containing a negatively charged nido-carboranyl fragment bearing a positive charge on the sulfur atom associated with the boron cluster.

3-5-2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-ylpentan-1-ylthymidine (compound 1, N5-2OH) belongs to a novel class of boron delivery agents for neutron capture therapy, which was designated 3-carboranylthymidine analogue (3CTAs). Two shorter and more convenient synthetic routes were developed for the synthesis of 1in the 10B-enriched form, which is necessary for its preclinical and clinical evaluation in neutron irradiation studies. For more insight on structure−activity relationships, various stereochemical and geometrical isomers of 1were synthesized and their specificities as substrate for human thymidine kinase 1 (hTK1) were evaluated. A computational model for the binding of various isomers of 1 to the active site of hTK1 was developed. Preliminary studies carried out in F98 glioma bearing rats that had received a 10B-enriched form of 1followed by neutron irradiation demonstrated a significant prolongation in survival times compared to control animals, suggesting that further studies are warranted to evaluate the therapeutic potential of 1.

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10 is irradiated with low energy thermal neutrons to yield high linear energy transfer (LET) alpha particles (4He) and recoiling lithium -7(7Li) nuclei. For BNCT to be successful, a sufficient number of 10B atoms (∼ 109 atoms/cell) must be selectively delivered to the tumor and enough thermal neutrons must be absorbed by them to sustain a lethal 10B(n, α) 7Li capture reaction. BNCT primarily has been used to treat patients with brain tumors, and more recently those with head and neck cancer. Two low molecular weight (LMW) boron delivery agents currently are being used clinically, sodium borocaptate and boronophenylalanine. However, a variety of high molecular weight (HMW) agents consisting of macromolecules and nanovehicles have been developed. This review will focus on the latter which include: monoclonal antibodies, dendrimers, liposomes, dextrans, polylysine, avidin, folic acid, and epidermal and vascular endothelial growth factors (EGF and VEGF). Procedures for introducing boron atoms into these HMW agents and their chemical properties will be discussed. In vivo studies on their biodistribution will be described, and the efficacy of a subset of them, which have been used for BNCT of tumors in experimental animals, will be discussed. Since brain tumors currently are the primary candidates for treatment by BNCT, delivery of these HMW agents across the blood-brain barrier presents a special challenge. Various routes of administration will be discussed including receptor-facilitated transcytosis following intravenous administration, direct intratumoral injection and convection enhanced delivery by which a pump is used to apply a pressure gradient to establish bulk flow of the HMW agent during interstitial infusion. Finally, we will conclude with a discussion relating to issues that must be addressed if these HMW agents are to be used clinically.

Abstract Boron neutron capture therapy (BNCT) is dependent on the selective accumulation of boron-10 in tumour cells. To maximise the radiation effect, the neutrons should be delivered when the ratio between the boron concentration in tumour cells to that in normal tissues reaches maximum. However, the pharmacokinetics of p-boronophenylalanine (BPA) and other boron delivery agents are only partly known. We used microdialysis to investigate the extracellular in vivo kinetics of boron in three intracerebral compartments -- solid tumour, brain adjacent to tumour (BAT), and the normal brain, as well as the subcutaneous tissue before, during, and after BNCT treatment. The findings were compared to the pharmacokinetics of BPA in the blood. We also measured the glucose metabolism and the levels of glutamate and glycerol in those compartments. Four patients were studied, two patients underwent surgical tumour resection and in two a stereotactic biopsy was performed. The patients were given BPA (900 mg/kg body weight) by a 6--h infusion. The infusion was completed approximately 2--3 h before neutron irradiation. In tumour tissue the extracellular concentration of BPA followed that of blood with a maximal concentration of 31.2 ppm and a maximal ratio vs. blood of 1.07. In BAT, the maximal concentration of BPA was 18.0 ppm with the peak level delayed for 4--6 h compared to the peak in blood with a maximal ratio of 1.2. Maximal blood concentration found was 41.0 ppm. The uptake of BPA in the normal brain was considerably lower than that in the blood and tumour tissue. No change in glucose metabolism was observed. The extracellular level of glycerol was increased after treatment in tumour tissue but not in normal brain suggesting a selective acute cytotoxic effect of BNCT on tumour cells.

Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH3⁺-nido-m-carborane-substituted thymidine analogues (Thds) and the corresponding neutral NH2-closo-m-carborane-substituted counterparts. All compounds of this library were good substrates for recombinant human thymidine kinase 1 (TK1) with phosphorylation rates up to 89% relative to that of Thd. One compound out of this library, 3-[3-(7-NH3⁺-nido-m-carboran-1-yl)propan-1-yl]thymidine (19b), showed selective retention in TK1-expressing murine L929 wild-type tumors versus L929 TK1 (−) tumors in biodistribution studies. The biological evaluation of the zwitterionic NH3⁺-nido-m-carborane-substituted Thds indicated improved aqueous solubility and similar or even superior potential as BNCT agents compared with different classes of 3CTAs (Cancer Res. 2004, 64, 6280−6286 and 6287−6295). To complete previous structure−activity relationship (SAR) studies, 3-[(closo-o-carboranyl)methyl]thymidine (4) was also synthesized and evaluated.

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.

A pre-clinical characterization of the first fission converter based epithermal neutron beam (FCB) designed for boron neutron capture therapy (BNCT) has been performed. Calculated design parameters describing the physical performance of the aluminium and Teflon® filtered beam were confirmed from neutron fluence and absorbed dose rate measurements performed with activation foils and paired ionization chambers. The facility currently provides an epithermal neutron flux of 4.6 × 10⁹ n cm⁻² s⁻¹ in-air at the patient position that makes it the most intense BNCT source in the world. This epithermal neutron flux is accompanied by very low specific photon and fast neutron absorbed doses of 3.5 ± 0.5 and 1.4 ± 0.2 × 10⁻¹³ Gy cm², respectively. A therapeutic dose rate of 1.7 RBE Gy min⁻¹ is achievable at the advantage depth of 97 mm when boronated phenylalanine (BPA) is used as the delivery agent, giving an average therapeutic ratio of 5.7. In clinical trials of normal tissue tolerance when using the FCB, the effective prescribed dose is due principally to neutron interactions with the nonselectively absorbed BPA present in brain. If an advanced compound is considered, the dose to brain would instead be predominately from the photon kerma induced by thermal neutron capture in hydrogen and advantage parameters of 0.88 Gy min⁻¹, 121 mm and 10.8 would be realized for the therapeutic dose rate, advantage depth and therapeutic ratio, respectively. This study confirms the success of a new approach to producing a high intensity, high purity epithermal neutron source that attains near optimal physical performance and which is well suited to exploit the next generation of boron delivery agents.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with neutrons of the appropriate energy to produce high-energy alpha particles and recoiling lithium-7 nuclei. BNCT has been used clinically to treat patients with high-grade gliomas, and a much smaller number with primary and metastatic melanoma. The purpose of this special issue of the Journal of Neuro-Oncology is to provide a critical and realistic assessment of various aspects of basic and clinical BNCT research in order to better understand its present status and future potential. Topics that are covered include neutron sources, tumor-targeted boron delivery agents, brain tumor models to assess therapeutic efficacy, computational dosimetry and treatment planning, results of clinical trails in the United States, Japan and Europe, pharmacokinetic studies of sodium borocaptate and boronophenylalanine (BPA), positron emission tomography imaging of BPA for treatment planning, and finally an overview of the challenges and problems that must be faced if BNCT is to become a useful treatment modality for brain tumors. Clinical studies have demonstrated the safety of BNCT. The next challenge is an unequivocal demonstration of therapeutic efficacy in one or more of the clinical trails that either are in progress or are planned over the next few years.

Development of any therapeutic modality can be facilitated by the use of the appropriate animal models to assess its efficacy. This report primarily will focus on our studies using the F98 and 9L rat glioma models to evaluate the effectiveness of boron neutron capture therapy (BNCT) of brain tumors. Following intracerebral implantation the biological behavior of each tumor resembles that of human high grade gliomas in a number of ways. In both models, glioma cells were implanted intracerebrally into syngeneic Fischer rats and ∼10–14 days later BNCT was initiated at the Brookhaven National Laboratory Medical Research Reactor. Two low molecular weight (Mr< 210 Da) 10B-containing drugs, boronophenylalanine (BPA) and/or sodium borocaptate (BSH) were used as capture agents, either alone or in combination with each other. The 9L gliosarcoma, which has been difficult to cure by means of either chemo- or radiotherapy alone, was readily curable by BNCT. The best survival data were obtained using BPA at a dose of 1200 mg/kg (64.8 mg 10B), administered intraperitoneally (i.p.), with a 100% survival rate at 8 months. In contrast, the F98 glioma has been refractory to all therapeutic modalities. Tumor bearing animals, which had received 500 mg/kg (27 mg 10B) of BPA, or an equivalent amount of BSH i.v., had mean survival time (MST) of 37 and 33 days, respectively, compared to 29 days for irradiated controls. The best survival data with the F98 glioma model were obtained using BPA + BSH in combination, administered intra-arterially via the internal carotid artery (i.c.) with hyperosmotic mannitol induced blood–brain barrier disruption (BBB-D). The MST was 140 days with a cure rate of 25%, compared to a MST of 73 days with a 5% cure rate without BBB-D, and 41 days following i.v. administration of both drugs. A modest but significant increase in MST also was observed in rats that received intracarotid (i.c.) BPA in combination with Cereport (RMP-7), which produced a pharmacologically mediated opening of the BBB. Studies also have been carried out with the F98 glioma to determine whether an X-ray boost could enhance the efficacy of BNCT, and it was shown that there was a significant therapeutic gain. Finally, molecular targeting of the epidermal growth factor receptor (EGFR) has been investigated using F98 glioma cells, which had been transfected with the gene encoding EGFR and, intratumoral injection of boronated EGF as the delivery agent, followed by BNCT. These studies demonstrated that there was specific targeting of EGFR and provided proof of principle for the use of high molecular weight, receptor targeting-boron delivery agents. Finally, a xenograft model for melanoma metastatic to the brain has been developed using a human melanoma (MRA27), stereotactically implanted into the brains of nude rats, and these studies demonstrated that BNCT either cured or significantly prolonged the survival of tumor-bearing rats. It remains to be determined, which, if any, of these experimental approaches will be translated into clinical studies. Be that as it may, rat brain tumor models already have made a significant contribution to the design of clinical BNCT protocols, and should continue to do so in the future.

The syntheses of two novel para-carboranyl and two novel nido-carboranyl phenanthridinium compounds as potential boron delivery agents for Neutron Capture Therapy are described

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 alpha particles and recoiling lithium-7 nuclei. High-grade astrocytomas, glioblastoma multiforme, and metastatic brain tumors constitute a major group of neoplasms for which there is no effective treatment. There is growing interest in using BNCT in combination with surgery to treat patients with primary, and possibly metastatic brain tumors. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must reach and be absorbed by the 10B atoms to sustain a lethal 10B (n,α) 7Li reaction. Two major questions will be addressed in this review. First, how can a large number of 10B atoms be delivered selectively to cancer cells? Second, how can a high fluence of neutrons be delivered to the tumor? Two boron compounds currently are being used clinically, sodium borocaptate (BSH) and boronophenylalanine (BPA), and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These will be discussed, and potential problems associated with their use as boron delivery agents will be considered. Nuclear reactors, currently, are the only source of neutrons for BNCT, and the fission process within the core produces a mixture of lower-energy thermal and epithermal neutrons, fast or high (>10,000 eV) energy neutrons, and gamma rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams should be more useful because of their superior tissue-penetrating properties. Beam sources and characteristics will be discussed in the context of current and future BNCT trials. Finally, the past and present clinical trials on BNCT for brain tumors will be reviewed and the future potential of BNCT will be assessed.

The polyhedral borane ion [n-B20H18]2- reacts with liquid ammonia in the presence of a suitable base to produce an apical-equatorial (ae) isomer of the [B20H17NH3]3- ion, [1-(2'-B10H9)-2-NH3B10H8]3-. The structure of this product has been confirmed by 11B NMR spectroscopy and x-ray crystallography. This species undergoes acid-catalyzed rearrangement to an apical-apical (a2) isomer, [1-(1'-B10H9)-2-NH3B10H8]3-, whose structure has been determined by 11B NMR spectroscopy. The sodium salts of both the ae and the a2 isomers of [B20H17NH3]3- have been encapsulated within small unilamellar liposomes, composed of distearoyl phosphatidylcholine/cholesterol (1:1), and investigated as boron-delivery agents for boron neutron capture therapy (BNCT) of cancer. The biodistribution of boron was determined after the injection of liposomal suspensions into BALB/c mice bearing EMT6 tumors. Both [B20H17NH3]3- isomers exhibited excellent tumor uptake and selectivity at very low injected doses, achieving peak tumor boron concentrations of 30-40 micrograms of B/g of tissue and tumor/blood boron ratios of approximately 5. The enhanced retention of the [B20H17NH3]3- isomers by EMT6 tumors may be attributed to their facile intracellular oxidation to an extremely reactive NH3-substituted [n-B20H18]2- ion, the electrophilic [B20H17NH3]- ion. Both isomers of [B20H17NH3]3- are at least 0.5 V more easily oxidized than other previously investigated species containing 20 boron atoms. In another experiment, [ae-B20H17NH3]3- was encapsulated in liposomes prepared with 5% PEG-2000-distearoyl phosphatidylethanolamine in the liposome membrane. As expected, these liposomes exhibited a longer circulation lifetime in the biodistribution experiment, resulting in the continued accumulation of boron in the tumor over the entire 48-hr experiment and reaching a maximum of 47 micrograms of B/g of tumor.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low energy (0.025 eV) thermal neutrons (nth) to yield alpha (4He) particles and,7Li nuclei (10B+nth→[11B]→4He+7Li+2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of10B andnthto individual cancer cells to sustain a lethal10B(n, α)7Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium borocaptate (Na2B12H11SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a “starburst” dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing, nucleosides are potential vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting therapeutic efficacy.

Two porphyrin–cobaltacarborane conjugates 5and 6were prepared in high yields viaa nucleophilic ring-opening reaction of 2. These novel boron-rich and fluorescent compounds have potential application as boron delivery agents for the boron neutron capture therapy of tumors.

Keywords: Boron Neutron Capture Therapy; Cancer; Health and Medicine; High-Energy Radiotherapy; Neutron Capture Therapy; Oncology; Radiotherapy EN Boron Neutron Capture Therapy Cancer Health and Medicine High-Energy Radiotherapy Neutron Capture Therapy Oncology Radiotherapy 1268 1268 1 05/08/23 20230512 NES 230512 2023 MAY 9 (NewsRx) -- By a News Reporter-Staff News Editor at Drug Week -- Fresh data on neutron capture therapy are presented in a new report. Boron Neutron Capture Therapy, Cancer, Health and Medicine, High-Energy Radiotherapy, Neutron Capture Therapy, Oncology, Radiotherapy. [Extracted from the article]

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An experimental form of radiation therapy could more effectively target lethal cancers. Scientists from the Idaho National Engineering and Environmental Laboratory, collaborating with scientists from Argentina, developed Boron Neutron Capture [...]