boron and Neoplasms

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.

Topics: Boron; Boron Neutron Capture Therapy; Contrast Media; Humans; Liposomes; Neoplasms

Boron neutron capture therapy (BNCT) is one of the most promising treatments among neutron capture therapies due to its long-term clinical application and unequivocally obtained success during clinical trials. Boron drug and neutron play an equivalent crucial role in BNCT. Nevertheless, current clinically used l-boronophenylalanine (BPA) and sodium borocaptate (BSH) suffer from large uptake dose and low blood to tumor selectivity, and that initiated overwhelm screening of next generation of BNCT agents. Various boron agents, such as small molecules and macro/nano-vehicles, have been explored with better success. In this featured article, different types of agents are rationally analyzed and compared, and the feasible targets are shared to present a perspective view for the future of BNCT in cancer treatment. This review aims at summarizing the current knowledge of a variety of boron compounds, reported recently, for the application of BCNT.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Neoplasms

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

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Neoplasms; Radiobiology

Boron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1α, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies.

Topics: Antineoplastic Agents; Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Neoplasms

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are potent technologies for non-invasive imaging of pharmacological and biochemical processes in both preclinical and advanced clinical research settings. In the field of radiation therapy, boron neutron capture therapy (BNCT) stands out because it harnesses biological mechanisms to precisely target tumor cells while preserving the neighboring healthy tissues. To achieve the most favorable therapeutic outcomes, the delivery of boron-enriched tracers to tumors must be selective and efficient, with a substantial concentration of boron atoms meticulously arranged in and around the tumor cells. Although several BNCT tracers have been developed to facilitate the targeted and efficient delivery of boron to tumors, only a few have been labeled with PET or SPECT radionuclides. Such radiolabeling enables comprehensive

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Neoplasms; Positron-Emission Tomography

Cancer is currently the second leading cause of death globally. Despite multidisciplinary efforts, therapies to fight various types of cancer still remain inefficient. Reducing high recurrence rates and mortality is thus a major challenge to tackle. In this context, redox imbalance is an undervalued characteristic of cancer. However, it may be targeted by boron- and phosphorus-containing materials to selectively or systemically fight cancer. In particular, boron and phosphorus derivatives are attractive building blocks for rational drug discovery due to their unique and wide regioselective chemistry, high degree of tuneability and chemical stability. Thus, they can be meticulously employed to access tunable molecular platforms to selectively exploit the redox imbalance of cancer cells towards necrosis/apoptosis. This field of research holds a remarkable potential; nevertheless, it is still in its infancy. In this mini-review, we underline recent advances in the development of boron- or phosphorus-derivatives as molecular/nano platforms for rational anticancer drug design. Our goal is to provide comprehensive information on different methodologies that bear an outstanding potential to further develop this very promising field of research.

Topics: Boron; Neoplasms; Phosphorus

Boron neutron capture therapy is a low-invasive cancer therapy based on the neutron fission process that occurs upon thermal neutron irradiation of

Topics: Boron; Boron Neutron Capture Therapy; Drug Delivery Systems; Humans; Neoplasms; Neutrons

Boron dipyrromethene (BODIPY), as a traditional fluorescent dye, has drawn increasing attention because of its excellent photophysical properties like adjustable spectra and outstanding photostability. BODIPY dyes could be assembled into nanoparticles for cancer imaging and therapy via rational design. In this review, the bio-applications of BODIPY-containing nanoparticles are introduced in detail, such as cellular imaging, near-infrared fluorescence imaging, computed tomography imaging, photoacoustic imaging, phototherapy, and theranostics. The construction strategies of BODIPY-containing nanoparticles are emphasized so the review has three sections-self-assembly of small molecules, chemical conjugation with hydrophilic compounds, and physical encapsulation. This review not only summarizes various and colorific bio-applications of BODIPY-containing nanoparticles, but also provides reasonable design methods of BODIPY-containing nanoparticles for cancer theranostics. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging.

Topics: Animals; Boron; Diagnostic Imaging; Drug Compounding; Humans; Nanoparticles; Neoplasms; Porphobilinogen

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Glioblastoma; Humans; Isotopes; Melanoma; Neoplasms; Phenylalanine; Positron-Emission Tomography

As traditional phototherapy agents, boron dipyrromethene (BODIPY) photosensitizers have attracted increasing attention due to their high molar extinction coefficients, high phototherapy efficacy, and excellent photostability. After being formed into nanostructures, BODIPY-containing nano-photosensitizers show enhanced water solubility and biocompatibility as well as efficient tumor accumulation compared to BODIPY molecules. Hence, BODIPY nano-photosensitizers demonstrate a promising potential for fighting cancer. This review contains three sections, classifying photodynamic therapy (PDT), photothermal therapy (PTT), and the combination of PDT and PTT based on BODIPY nano-photosensitizers. It summarizes various BODIPY nano-photosensitizers, which are prepared via different approaches including molecular precipitation, supramolecular interactions, and polymer encapsulation. In each section, the design strategies and working principles of these BODIPY nano-photosensitizers are highlighted. In addition, the detailed in vitro and in vivo applications of these recently developed nano-photosensitizers are discussed together with future challenges in this field, highlighting the potential of these promising nanoagents for new tumor phototherapies.

Topics: Animals; Antineoplastic Agents; Boron; Humans; Neoplasms; Photosensitizing Agents; Phototherapy; Porphobilinogen

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.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Isotopes; Liposomes; Neoplasms; Neutrons; Tissue Distribution

Gadolinium neutron capture therapy (Gd-NCT) is currently under development as an alternative approach for cancer therapy. All of the clinical experience to date with NCT is done with (10)B, known as boron neutron capture therapy (BNCT), a binary treatment combining neutron irradiation with the delivery of boron-containing compounds to tumors. Currently, the use of Gd for NCT has been getting more attention because of its highest neutron cross-section. Although Gd-NCT was first proposed many years ago, its development has suffered due to lack of appropriate tumor-selective Gd agents. This review aims to highlight the recent advances for the design, synthesis and biological testing of new Gd- and B-Gd-containing compounds with the task of finding the best systems able to improve the NCT clinical outcome.

Topics: Boron; Gadolinium; Humans; Neoplasms; Neutron Capture Therapy

  High accumulation and selective delivery of boron into tumor tissue are the most important requirements to achieve the efficient cell-killing effect of boron neutron capture therapy (BNCT) that relies on the nuclear reaction of two essentially nontoxic species, boron-10 ((10)B) and thermal neutrons in boron-loaded tissues. Recent development of boron cluster lipids and their liposomal boron delivery system (BDS) are summarized in this article. Boron compounds that have no affinity to tumor can potentially be delivered to tumor tissues by liposomes, therefore, liposomal BDS would be one of the most attractive approaches for efficient BNCT of various cancers. There are two approaches for BDS: encapsulation of boron compounds into liposomes and incorporation of boron-conjugated lipids into the liposomal bilayer. The combination of both approaches has a potential for reduction of the total dose of liposomes without reducing the efficacy of BNCT.

Topics: Animals; Antineoplastic Agents; Boron; Boron Neutron Capture Therapy; Drug Carriers; Humans; Liposomes; Neoplasms

Topics: Boron; Boron Neutron Capture Therapy; Humans; Isotopes; Japan; Neoplasms; Neutrons; Particle Accelerators; Radiopharmaceuticals; Research

The cell-killing effect of boron neutron capture therapy (BNCT) is due to the nuclear reaction of two essentially nontoxic species, boron-10 ((10)B) and thermal neutrons, whose destructive effect is well observed in boron-loaded tissues. High accumulation and selective delivery of boron into tumor tissue are the most important requirements to achieve efficient neutron capture therapy of cancers. This review focuses on liposomal boron delivery system (BDS) as a recent promising approach that meet these requirements for BNCT. BDS involves two strategies: (1) encapsulation of boron in the aqueous core of liposomes and (2) accumulation of boron in the liposomal bilayer. In this review, recent development of liposomal boron delivery system is summarized.

Topics: Animals; Boron; Boron Neutron Capture Therapy; Drug Delivery Systems; Liposomes; Mice; Mice, Inbred BALB C; Neoplasms

This review covers the application of cycloaddition reactions in forming the boron-containing compounds such as symmetric star-shaped boron-enriched dendritic molecules, nano-structured boron materials and aromatic boronic esters. The resulting boron compounds are potentially important reagents for both materials science and medical applications such as in boron neutron capture therapy (BNCT) in cancer treatment and as drug delivery agents and synthetic intermediates for carbon-carbon cross-coupling reactions. In addition, the use of boron cage compounds in a number of cycloaddition reactions to synthesize unique aromatic species will be reviewed briefly.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Drug Delivery Systems; Humans; Neoplasms

Topics: Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Boron; Boron Compounds; Boron Neutron Capture Therapy; Boronic Acids; Bortezomib; Carbon; Drug Design; Humans; Molecular Structure; Neoplasms; Protease Inhibitors; Pyrazines

The main objective of this paper is to evaluate the scientific evidence on the form of organic boron, calcium fructoborate (CF), including health dates, dietary needs, pharmacology, experts opinion, research papers, clinical evidence, and dosing. CF is a natural product with effects in oxidative metabolism and cell apoptosis. We review the biological and biochemical action of chemical natural-identical entity of CF. This mini review provides support for future clinical research.

Topics: Animals; Antioxidants; Apoptosis; Arthritis; Borates; Boron; Dietary Supplements; Fructose; Humans; Neoplasms; Oxidative Stress; Plant Preparations; Plants; Trace Elements

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Drug Delivery Systems; Humans; Liposomes; Neoplasms; Phenylalanine; Positron-Emission Tomography

Boron Neutron Capture Therapy (BNCT) is based on the ability of the stable isotope 10B to capture neutrons, which leads to a nuclear reaction producing an alpha- and a 7Li-particle, both having a high biological effectiveness and a very short range in tissue, being limited to approximately one cell diameter. This opens the possibility for a highly selective cancer therapy. BNCT strongly depends on the selective uptake of 10B in tumor cells and on its distribution inside the cells. The chemical properties of boron and the need to discriminate different isotopes make the investigation of the concentration and distribution of 10B a challenging task. The most advanced techniques to measure and image boron are described, both invasive and non-invasive. The most promising approach for further investigation will be the complementary use of the different techniques to obtain the information that is mandatory for the future of this innovative treatment modality.

Topics: Autoradiography; Boron; Boron Neutron Capture Therapy; Humans; Isotopes; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mass Spectrometry; Neoplasms; Positron-Emission Tomography; Radiobiology; Spectrometry, Gamma; Spectrophotometry, Atomic; Spectroscopy, Electron Energy-Loss; Tissue Distribution

In an investigation by the Swedish Cancer Society, an expert group described the present status, critical issues and future aspects and potentials for each of nine major areas of radiation therapy research. This report deals with radiation therapy using activation of stable nuclides.

Topics: Boron; Gadolinium; Glioma; Humans; Isotopes; Melanoma; Neoplasms; Neutron Capture Therapy

The boron neutron capture therapy is based on the reaction occurring with certain probability, if a thermal neutron meets the boron 10 isotope. The low energy slow neutron is captured by the nucleus and it disintegrates into Li-nucleus and He-nucleus (alpha particle). If this physical reaction occurs in a living cell that will be destroyed. If the boron neutron capture reaction could be achieved selectively in malignant cells of tumor patients, that could be an effective therapeutical modality to treat the locally growing cancers. For boron neutron capture therapy to be successful two basic conditions must be fulfilled, an appropriate neutron source must be available and the sufficient number of 10B must be delivered possibly selectively into the tumor cells by a boron compound. At present both part of this binary system are under intensive investigation, the development of the neutron source, the synthetisation and experimental testing of boron delivery agents. The development of the dosimetry, microdosimetry, the work out of the powerful tools of detection the cellular, subcellular 10B distribution, the continuous improvement of the planning system and the optimization of the boron neutron capture therapy are the main point of the research area on boron neutron capture therapy. Clinical studies and clinical application of boron neutron capture therapy are under way for the treatment of melanoma malignum and for brain tumors, with the two boron compound has been clinically tested up to now, in Japan, at two Centres in USA, and recently has been started in Europe. The authors give an overview about the principles of boron neutron capture therapy, about the result of the research on neutron sources and boron compounds, moreover about the possible application area of this new radiation modality.

Topics: Boron; Humans; Neoplasms; Neutrons; Radioisotopes; Trace Elements

Topics: Boron; Boron Neutron Capture Therapy; Humans; Neoplasms

Boron neutron capture therapy (BNCT) is a mode of radiotherapy with great attractiveness, but also with a burden of past failure. In this review, the principles of BNCT, the reasons for its past failure, its present clinical application, and the on-going developmental work towards clinical trials are described.

Topics: Animals; Borohydrides; Boron; Boron Neutron Capture Therapy; Humans; Neoplasms; Sulfhydryl Compounds

The neutron capture reaction 10B(1n,4He)7Li produces two energetic particles, 4He2+ and 7Li3+ that are strongly cell toxic. Due to the short range of these nuclear fragments (5-9 microns) mainly those cells that have bound or internalized a 10B-containing substance are growth-inactivated. The most critical and difficult step in an efficient boron neutron capture therapy (BNCT) is the tumour targeting. It is today possible to synthesize a large number of boron compounds and conjugate them to tumour-seeking macromolecules, such as monoclonal antibodies or different polypeptides. The boron-containing substances presently considered for therapy are sulfhydryl boron hydride (BSH) and boron-phenylalanine, (BPA) for the treatment of gliomas and malignant melanomas respectively. Other boronated compounds considered are ligands for receptor-amplified tumour cells, antibodies for tumour cells with specific antigens and thioureas for treatment of melanotic melanomas. The required boron concentration is given by the relative dose due to neutron capture in 10B and that of the competing capture reactions in nitrogen and hydrogen. Capture in nitrogen produces protons with a range of about 10-11 microns and this gives a radiation dose to all cells in the neutron activated area. Calculations show that the local concentration of 10B near the critical radiation target, DNA, must be higher than 10 ppm (10 micrograms/g). Increased emphasis will be put on the development of combinations of treatments that fulfil the requirements for attacking the microscopic spread of the tumour.

Topics: Boron; Clinical Trials as Topic; Humans; Isotopes; Neoplasms; Neutron Capture Therapy; Radiotherapy Dosage

The resurgence of interest in neutron capture therapy, which uses boron-10 labelled compounds and neutron irradiation as a technique for the treatment of cancer, has been accompanied by the application of a new generation of techniques for the analysis and imaging of boron in biological matrices. In this review, a description is given of the requirements for boron neutron capture agents and the achievements to date of the analytical techniques.

Topics: Animals; Antineoplastic Agents; Boron; Calorimetry; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Neoplasms; Spectrophotometry, Atomic

Topics: Antimetabolites; Boron; Coloring Agents; Humans; Iodoacetates; Lithium; Neoplasms; Oxygen; Peroxides; Phenols; Radiation Protection; Radiation-Protective Agents; Radiation-Sensitizing Agents; Ribonucleases

Topics: Arsenic; Bismuth; Boron; Brain Neoplasms; Copper; Fluoresceins; Fluorine; Humans; Iodine Isotopes; Mercury; Neoplasms; Potassium Isotopes; Radioisotopes; Radionuclide Imaging; Rubidium; Serum Albumin; Serum Albumin, Radio-Iodinated

Topics: Boron; Clinical Trials as Topic; Humans; Isotopes; Neoplasms; Neutrons; Radiotherapy; USSR

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Neoplasms; Phenylalanine; Tissue Distribution; Water

Radiation therapy has been widely used in the clinical treatment of tumors. Due to the low radiation absorption of tumors, a high dose of ionizing radiation is often required during radiotherapy, which causes serious damage to normal tissues near tumors. Boron neutron capture therapy (BNCT) is more targeted than conventional radiotherapy. To improve the therapeutic effect of cancer, albumin was selected as the drug carrier to wrap the fluorescent tracer boron drug BS-CyP and prepare the nanoparticles. Then, we developed a novel tumor-targeting nano-boron drug by using hyaluronic acid to modify the nanoparticles. We found that BS-CyP albumin nanoparticles modified with hyaluronic acid effectively delayed drug release and enhanced the aggregation, in tumors, showing good safety with no obvious toxicity to cells and mice. This study confirmed the advantages of boron drugs modified with hyaluronic acid targeting tumors and may provide a reference for BNCT.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Hyaluronic Acid; Mice; Nanoparticles; Neoplasms

Boron neutron capture therapy shows is a promising approach to cancer therapy, but the delivery of effective boron agents is challenging. To address the requirements for efficient boron delivery, we used a hybrid nanoparticle comprising a carborane = bearing pullulan nanogel and hydrophobized boron oxide nanoparticle (HBNGs) enabling the preparation of highly concentrated boron agents for efficient delivery. The HBNGs showed better anti-cancer effects on Colon26 cells than a clinically boron agent, L-BPA/fructose complex, by enhancing the accumulation and retention amount of the boron agent within cells in vitro. The accumulation of HBNGs in tumors, due to the enhanced permeation and retention effect, enabled the delivery of boron agents with high tumor selectivity, meeting clinical demands. Intravenous injection of boron neutron capture therapy (BNCT) using HBNGs decreased tumor volume without significant body weight loss, and no regrowth of tumor was observed three months after complete regression. The therapeutic efficacy of HBNGs was better than that of L-BPA/fructose complex. BNCT with HBNGs is a promising approach to cancer therapeutics.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Fructose; Humans; Nanogels; Neoplasms

Boron neutron capture therapy (BNCT) was clinically approved in 2020 and exhibits remarkable tumour rejection in preclinical and clinical studies. It is binary radiotherapy that may selectively deposit two deadly high-energy particles (

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Female; Immunotherapy; Male; Mice; Neoplasms; Neutrons

This paper introduces the research of nanomachines utilizing boron chemistry. Boron neutron capture therapy (BNCT) has beeing attracting increasing attention as a minimally invasive cancer treatment, and p-boronophenylalanine (BPA) has been approved as a potent BNCT drug. However, intratumoral retention of BPA remains to be improved. Recently, we have developed a BPA delivery system [poly vinyl alcohol (PVA)-BPA] utilizing PVA. PVA-BPA altered the uptake pathway of BPA by cancer cells and significantly improved the intracellular retention in cancer cells. in the in vivo experiments, PVA-BPA showed improved tumor accumulation and a remarkable tumor growth inhibition upon thermal neutron irradiation. On the other hand, a useful delivery system of bioactive proteins has been strongly demanded. In this study, we have developed the ternary complex micelles for the protein delivery utilizing tannic acid (TA) and block copolymer containing a boronic acid group. The ternary micelles improved the blood retention and tumor accumulation of the loaded proteins, and realized a tumor tissue-selective enzymatic reaction in the enzyme delivery.

Topics: Biological Transport; Boron; Micelles; Neoplasms; Polymers; Polyvinyl Alcohol

Boron neutron capture therapy (BNCT) is a cancer treatment option that combines preferential uptake of a boron compound in tumors and irradiation with thermal neutrons. For treatment planning, the boron concentration in different tissues must be considered. Neutron autoradiography using nuclear track detectors (NTD) can be applied to study both the concentration and microdistribution of boron in tissue samples. Histological sections are obtained from frozen tissue by cryosectioning. When the samples reach room temperature, they undergo an evaporation process, which leads to an increase in the boron concentration. To take this effect into account, certain correction factors (evaporation coefficients, CEv) must be applied. With this aim, a protocol was established to register and analyze mass variation of tissue sections, measured with a semimicro scale. Values of ambient temperature, pressure, and humidity were simultaneously recorded. Reproducible results of evaporation curves and CEv values were obtained for different tissue samples, which allowed the systematization of the procedure. This study could contribute to a more precise determination of boron concentration in tissue samples through the neutron autoradiography technique, which is of great relevance to make dosimetric calculations in BNCT.

Topics: Autoradiography; Boron; Boron Neutron Capture Therapy; Humans; Neoplasms; Neutrons

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.

Topics: Boranes; Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Monosaccharides; Neoplasms

Phototheranostics integrating optical imaging and phototherapy has attracted extensive attention. Achieving nanophototherapeutics with near infrared (NIR)-light synchronously triggered photodynamic therapy (PDT) and photothermal therapy (PTT) is challenging. Herein, we develop a multifunctional theranostic nanoplatform prepared from the co-assembly of NIR boron dipyrromethene (BODIPY) with a cooperative D-π-A structure of a thiophene-BODIPY core and benzene-diethylamino, and a choline phosphate lipid. The as-fabricated nanoparticles (DBNPs) exhibited desirable NIR absorption, uniform spherical morphology and good colloidal stability. The elaborate molecular design and supramolecular assembly endowed DBNPs with desirable PDT and PTT activities. Upon 808 nm laser irradiation, the DBNPs efficiently generated active singlet oxygen and regional hyperpyrexia, with a photothermal conversion efficiency of 37.6%. The excellent PDT and PTT performance of DBNPs boosted the potent

Topics: Boron; Humans; Lipids; Nanoparticles; Neoplasms; Optical Imaging; Phosphorylcholine

BNCT is considered to be a promising method for the treatment of malignant tumors, which ensures the selective destruction of malignant tumor cells by accumulating non-radioactive atomic boron-10 nuclei in them and subsequent irradiation with neutrons. As a result of the absorption of a neutron by boron, a nuclear reaction occurs with the release of energy in a cell containing boron, which leads to its death. To date, two drugs for targeted delivery of boron, boronophenylalanine and sodium borocaptate, have been developed, which ensures selective accumulation of boron in a number of tumors, and a number of charged particle accelerators with neutron-generating targets and with neutron beam shaping assemblies have been developed providing the quality of the neutron beam required for therapy. The paper presents a critical analysis of the methods used to form a therapeutic neutron beam and proposes a new concept of a neutron beam shaping assembly, supported by the results of numerical simulation validated by in-phantom measurements.

Topics: Animals; Borohydrides; Boron; Boron Neutron Capture Therapy; Neoplasms; Neutrons

Ferroptosis is a form of programmed cell death and plays an important role in many diseases. Dihydroorotate dehydrogenase (DHODH) and glutathione peroxidase 4 (GPX4) play major roles in cell resistance to ferroptosis. Therefore, inactivation of these proteins provides an excellent opportunity for efficient ferroptosis-based synergistic cancer therapy. In this study, a multifunctional nanoagent (BPN

Topics: Boron; Dihydroorotate Dehydrogenase; Ferroptosis; Humans; Neoplasms

Boron neutron capture therapy (BNCT), advanced cancer treatment utilizing nuclear fission of

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Glycerol; Mice; Nanodiamonds; Neoplasms

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

Topics: Biological Transport; Boron; Boron Neutron Capture Therapy; Humans; Neoplasms; Neutrons

Noninvasive monitoring of boron agent biodistribution is required in advance of neutron capture therapy. In this study, we developed a gadolinium-boron-conjugated albumin (Gd-MID-BSA) for MRI-guided neutron capture therapy. Gd-MID-BSA was prepared by labeling bovine serum albumin with a maleimide-functionalized gadolinium complex and a maleimide-functionalized

Topics: Animals; Boron; Boron Neutron Capture Therapy; Gadolinium; Magnetic Resonance Imaging; Maleimides; Mice; Neoplasms; Neutron Capture Therapy; Tissue Distribution

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.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Copper Radioisotopes; Humans; Liposomes; Neoplasms; Penicillins

Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7-870 μM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver β-glucosidase and β-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cattle; Glycoside Hydrolases; Neoplasms; Rats

The recent interaction cross-section-based formulation for radiation-induced direct cellular inactivation, mild and severe sublethal damage, DNA-repair and cell survival have been developed to accurately describe cellular repair, misrepair and apoptosis in TP53 wild-type and mutant cells. The principal idea of this new non-homologous repairable-homologous repairable (RHR) damage formulation is to separately describe the mild damage that can be rapidly handled by the most basic repair processes including the non-homologous end joining (NHEJ), and more complex damage requiring longer repair times and high-fidelity homologous recombination (HR) repair. Taking the interaction between these two key mammalian DNA repair processes more accurately into account has significantly improved the method as indicated in the original publication. Based on the principal mechanisms of 7 repair and 8 misrepair processes presently derived, it has been possible to quite accurately describe the probability that some of these repair processes when unsuccessful can induce cellular apoptosis with increasing doses of γrays, boron ions and PRIMA-1. Interestingly, for all LETs studied (≈0.3-160 eV/nm) the increase in apoptosis saturates when the cell survival reaches about 10% and the fraction of un-hit cells is well below the 1% level. It is shown that most of the early cell kill for low-to-medium LETs are due to apoptosis since the cell survival as well as the non-apoptotic cells agree very well at low doses and other death processes dominate beyond D > 1 Gy. The low-dose apoptosis is due to the fact that the full activation of the checkpoint kinases ATM and Chk2 requires >8 and >18 DSBs per cell to phosphorylate p53 at serine 15 and 20. Therefore, DNA repair is not fully activated until well after 1/2 Gy, and the cellular response may be apoptotic by default before the low-dose hyper sensitivity (LDHS) is replaced by an increased radiation tolerance as the DNA repair processes get maximal efficiency. In effect, simultaneously explaining the LDHS and inverse dose rate phenomena. The partial contributions by the eight newly derived misrepair processes was determined so they together accurately described the experimental apoptosis induction data for γ rays and boron ions. Through these partial misrepair contributions it was possible to predict the apoptotic response based solely on carefully analyzed cell survival data, demonstrating the usefulness of an accurate DNA repair-based ce

Topics: Animals; Apoptosis; Aza Compounds; Boron; Bridged Bicyclo Compounds, Heterocyclic; DNA Damage; DNA Repair; Fibroblasts; Gamma Rays; Ions; Linear Energy Transfer; Mammals; Mice; Neoplasms; Reactive Oxygen Species; Recombinational DNA Repair; Tumor Suppressor Protein p53

A series of novel cobalt bis(dicarbollide)-curcumin conjugates were synthesized. Two conjugates were obtained through the nucleophilic ring-opening reaction of the 1,4-dioxane and tetrahydropyran derivatives of cobalt bis(dicarbollide) with the OH group of curcumin, and using two equiv. of the oxonium derivatives, two other conjugates containing two cobalt bis(dicarbollide) units per molecule were obtained. In contrast to curcumin, the conjugates obtained were found to be non-cytotoxic against both tumor and normal cell lines. The analysis of the intracellular accumulation of the conjugates by flow cytometry showed that all cobalt bis(dicarbollide)-curcumin conjugates entered HCT116 colorectal carcinoma cells in a time-dependent manner. New non-cytotoxic conjugates contain a large amount of boron atoms in the biomolecule and can potentially be used for further biological research into boron neutron capture therapy (BNCT).

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Cobalt; Curcumin; Humans; Neoplasms

While boron neutron capture therapy (BNCT) depends primarily on the short flight range of the alpha particles emitted by the boron neutron capture reaction, gadolinium neutron capture therapy (GdNCT) mainly relies on gamma rays and Auger electrons released by the gadolinium neutron capture reaction. BNCT and GdNCT can be complementary in tumor therapy. Here, we studied the combined effects of BNCT and GdNCT when boron and gadolinium compounds were co-injected, followed by thermal neutron irradiation, and compared these effects with those of the single therapies. In cytotoxicity studies, some additive effects (32‒43%) were observed when CT26 cells were treated with both boron- and gadolinium-encapsulated PEGylated liposomes (B- and Gd-liposomes) compared to the single treatments. The tumor-suppressive effect was greater when BNCT was followed by GdNCT at an interval of 10 days rather than vice versa. However, tumor suppression with co-injection of B- and Gd-liposomes into tumor-bearing mice followed by neutron beam irradiation was comparable to that observed with Gd-liposome-only treatment but lower than B-liposome-only injection. No additive effect was observed with the combination of BNCT and GdNCT, which could be due to the shielding effect of gadolinium against thermal neutrons because of its overwhelmingly large thermal neutron cross section.

Topics: Animals; Boron; Boron Compounds; Disease Models, Animal; Gadolinium; Liposomes; Mice; Neoplasms; Neutron Capture Therapy

The regulation of photochemical properties of phototheranostics, especially the absorption, fluorescence, singlet oxygen (

Topics: Boron; Boron Compounds; HeLa Cells; Humans; Nanoparticles; Neoplasms; Photoacoustic Techniques; Photothermal Therapy; Porphobilinogen

The presence of apoptosis inhibition proteins renders the cancer cells resistant to apoptosis, severely compromising the antitumor efficacy of sonodynamic therapy (SDT). Here, an intelligent anticancer nanoplatform based on an Aza-boron-dipyrromethene dye (denoted as Aza-BDY) is elaborately established for ferroptosis augmented SDT through cysteine (Cys) starvation. After endocytosis by tumor cells, Aza-BDY serves as both a ferroptosis inducing agent and a sonosensitizer for tumor treatment. The specific Cys response facilitates the disruption of redox homeostasis and initiation of cellular ferroptosis. Meanwhile, the released sonosensitizer causes efficient SDT and augments ferroptosis under ultrasound irradiation. Detailed in vitro and in vivo investigations demonstrate that the synergistic effect of Cys depletion and singlet oxygen (

Topics: Boron; Cell Line, Tumor; Cysteine; Ferroptosis; Humans; Nanoparticles; Neoplasms; Porphobilinogen; Reactive Oxygen Species; Singlet Oxygen

Hypoxia-activated prodrugs (HAPs) have drawn increasing attention for improving the antitumor effects while minimizing side effects. However, the heterogeneous distribution of the hypoxic region in tumors severely impedes the curative effect of HAPs. Additionally, most HAPs are not amenable to optical imaging, and it is difficult to precisely trace them in tissues. Herein, we carefully designed and synthesized a multifunctional therapeutic

Topics: Azo Compounds; Boron; Boron Compounds; Camptothecin; Cell Line, Tumor; Humans; Hyperthermia, Induced; Hypoxia; Nanoparticles; Neoplasms; Phototherapy; Photothermal Therapy; Porphobilinogen; Prodrugs

Cancer phototheranostics that combines diagnosis with phototherapy has emerged as a new mode of precise treatment. Nevertheless, taking highly effective phototheranostics into consideration, it is still a tremendous challenge to design multifunctional photothermal agents (PTAs) that combine the features of intensive near-infrared (NIR) absorption/emission, high photothermal conversion efficiency (PCE) and preferable tumor accumulation. Herein, seeking a convenient method to facilitate absorption red-shift, promote the accumulation of drugs in tumors and heighten the PCE appears to be particularly important for cancer theranostics. In this work, heavy-atom-free boron dipyrromethene (BODIPY) was assembled with F127 to fabricate ultra-small J-aggregated nanoparticles (named as BNPs). Compared to free BODIPY, BNPs exhibited 63 nm redshifted absorption, deep-tissue fluorescence imaging, enhanced cellular uptake, preferable tumor accumulation, elevated PCE, excellent photothermal stability and water dispersibility.

Topics: Boron; Cell Line, Tumor; Humans; Nanoparticles; Neoplasms; Theranostic Nanomedicine

Photodynamic therapy (PDT) is a clinically approved therapeutic modality that has shown great potential for the treatment of cancers owing to its excellent spatiotemporal selectivity and inherently noninvasive nature. However, PDT has not reached its full potential, partly due to the lack of ideal photosensitizers. A common molecular design strategy for effective photosensitizers is to incorporate heavy atoms into photosensitizer structures, causing concerns about elevated dark toxicity, short triplet-state lifetimes, poor photostability, and the potentially high cost of heavy metals. To address these drawbacks, a significant advance has been devoted to developing advanced smart photosensitizers without the use of heavy atoms to better fit the clinical requirements of PDT. Over the past few years, heavy-atom-free nonporphyrinoid photosensitizers have emerged as an innovative alternative class of PSs due to their superior photophysical and photochemical properties and lower expense. Heavy-atom-free nonporphyrinoid photosensitizers have been widely explored for PDT purposes and have shown great potential for clinical oncologic applications. Although many review articles about heavy-atom-free photosensitizers based on porphyrinoid structure have been published, no specific review articles have yet focused on the heavy-atom-free nonporphyrinoid photosensitizers.In this account, the specific concept related to heavy-atom-free photosensitizers and the advantageous properties of heavy-atom-free photosensitizers for cancer theranostics will be briefly introduced. In addition, recent progress in the development of heavy-atom-free photosensitizers, ranging from molecular design approaches to recent innovative types of heavy-atom-free nonporphyrinoid photosensitizers, emphasizing our own research, will be presented. The main molecular design approaches to efficient heavy-atom-free PSs can be divided into six groups: (1) the approach based on traditional tetrapyrrole structures, (2) spin-orbit charge-transfer intersystem crossing (SOCT-ISC), (3) reducing the singlet-triplet energy gap (Δ

Topics: Boron; Boron Compounds; Drug Design; Humans; Light; Naphthalimides; Neoplasms; Photochemotherapy; Photosensitizing Agents; Pyrroles; Quantum Theory; Singlet Oxygen

Photothermal therapy is a new type of tumor therapy with great potential. An ideal photothermal therapy agent should have high photothermal conversion effect, low biological toxicity, and degradability. The development of novel photothermal therapy agents with these properties is of great demand. In this study, we synthesized boron quantum dots (BQDs) with an ultrasmall hydrodynamic diameter. Both

Topics: Animals; Boron; Cell Line, Tumor; Mice, Inbred BALB C; Neoplasms; Photoacoustic Techniques; Photothermal Therapy; Quantum Dots; Theranostic Nanomedicine

The natural phenolic molecule caffeic acid, show promising effects on biological systems as an anti/pro-oxidant, anti-cancer, and anti-inflammatory agent. In nanoparticle functionalization designs, most organic nanoparticle coatings are utilized only for their ability to carry chemotherapeutics and targeting ligand. In this study, UV-light and auto-oxidation polymerization of caffeic acid on top of as-prepared gold nanoparticles was utilized to bring about a 5 nm multifunctional coating. The resulting polycaffeic acid (PCA) coating was used to conjugate both boronic acid containing compounds, chemotherapeutic bortezomib (BTZ) and cancer targeting ligand folate, while inducing mitochondrial reactive oxygen species that can damage intracellular proteins and DNA. This complements the drug payload, bortezomib's cell survival inhibition properties. The drug, targeting ligand, and coating complexation are all pH cleavable under acidic pH condition (<5.0) which can be found in a tumor and endosomal microenvironment. The in vitro and in vivo experiments demonstrated cancer cytotoxicity and tumor inhibiting properties of the developed nanomedicine.

Topics: Antineoplastic Agents; Boron; Cell Line, Tumor; Drug Delivery Systems; Gold; Metal Nanoparticles; Nanoparticles; Neoplasms; Phenol; Reactive Oxygen Species

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Nanomedicine; Neoplasms

Topics: Animals; Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Gadolinium; Gold; Humans; Metal Nanoparticles; Mice; Neoplasms; Theranostic Nanomedicine

G-protein-coupled receptors like the human Y

Topics: Boranes; Boron; Boron Neutron Capture Therapy; Drug Carriers; Drug Delivery Systems; HEK293 Cells; Humans; MCF-7 Cells; Neoplasms; Neuropeptide Y; Receptors, Neuropeptide Y

The paper outlines the first report of application of a differential pulse voltammetry for simultaneous quantification of clinically important molecular markers - tryptophan and its metabolite - kynurenine. The analytes were determined in less than 60 s at the boron-doped diamond electrode modified in situ with bismuth film (BiF/BDDE). Proper adjustment of a supporting electrolyte composition allowed to obtain good separation of tryptophan and kynurenine oxidation peaks that appeared at potential of 0.88 and 1.05 V (vs. Ag/AgCl), respectively. Studies using an optical profilometer have confirmed an increase in electrode surface area after deposition of Bi film. At the optimized conditions, the obtained detection limits of tryptophan and kynurenine were at 30 nM concentrations. The method was validated for linearity, precision, accuracy, selectivity and recovery. We have investigated an impact of numerous relevant interfering organic compounds (including amino acids and different tryptophan metabolites of kynurenine pathway) on voltammetric signals of the measured analytes. Finally, for proof-of-technology, the sensor was used for tryptophan and kynurenine quantification in culture medium collected from human cancer cell lines (breast MDA-MB-231 and ovary SK-OV-3). The target molecules were analyzed directly, without any sample preparation step. The sensor showed good accuracy in presence of the sample matrix components that was confirmed by high performance liquid chromatography measurements. Our work emphasizes the advantages of application of the herein proposed, easy to fabricate voltammetric sensor, instead of popular chromatographic assays or previously proposed potentiometric immunosensor. The method might serve for rapid assessment of kynurenine pathway activity in cancer cells.

Topics: Biosensing Techniques; Boron; Cell Culture Techniques; Cell Line, Tumor; Chromatography, High Pressure Liquid; Culture Media; Diamond; Electrochemical Techniques; Electrodes; Humans; Kynurenine; Neoplasms; Tryptophan

Intracellular concentration of reactive oxygen species (e.g., H

Topics: Antineoplastic Agents; Antioxidants; Boron; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Electrons; Ferrous Compounds; Humans; Hydrogen Peroxide; Inhibitory Concentration 50; Jurkat Cells; Lysosomes; Metallocenes; Mitochondria; Neoplasms; Oxygen; Prodrugs; Reactive Oxygen Species; Solubility; Spectrometry, Mass, Electrospray Ionization

Based on our previously published reports concerning the response of quiescent (Q) tumor cell populations to boron neutron capture therapy (BNCT), the heterogeneous microdistribution of 10B in tumors, which is influenced by the tumor microenvironment and the characteristics of the 10B delivery carriers, has been shown to limit the therapeutic effect of BNCT on local tumors. It was also clarified that the characteristics of 10B-carriers for BNCT and the type of combined treatment in BNCT can also affect the potential for distant lung metastases from treated local tumors. We reviewed the findings concerning the response of Q tumor cell populations to BNCT, mainly focusing on reports we have published so far, and we identified the mode of BNCT that currently offers the best therapeutic gain from the viewpoint of both controlling local tumor and suppressing the potential for distant lung metastasis. In addition, based on the finding that oxygenated Q tumor cells showed a large capacity to recover from DNA damage after cancer therapy, the interrelationship among the characteristics in Q tumor cell populations, tumor heterogeneity and cancer stemness was also discussed.

Topics: Animals; Apoptosis; Borohydrides; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cellular Senescence; DNA Damage; Humans; Isotopes; Ligands; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Oxygen; Tumor Microenvironment

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

Topics: Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Drug Carriers; Drug Liberation; Glucose; Glucose Transporter Type 1; Humans; Isotopes; Molecular Docking Simulation; Neoplasms

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Line, Tumor; Drug Carriers; Female; Humans; Integrin alphaVbeta3; Intravital Microscopy; Isotopes; Mice; Neoplasms; Peptides, Cyclic; Serum Albumin, Bovine; Xenograft Model Antitumor Assays

The shortcomings in Boron neutron capture therapy (BNCT) and Hyperthermia for killing the tumor cell desired for the synthesis of a new kind of material suitable to be first used in BNCT and later on enable the conditions for Hyperthermia to destroy the tumor cell. The desire led to the synthesis of large band gap semiconductor nano-size Boron-10 enriched crystals of hexagonal boron nitride (

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Hyperthermia, Induced; Isotopes; Microscopy, Electron, Transmission; Nanoparticles; Nanotechnology; Neoplasms; Photoelectron Spectroscopy; Quantum Dots; Spectrum Analysis, Raman; X-Ray Diffraction

Quantum dots (QDs) are increasingly being utilized as near infrared (NIR) active photothermal agents for cancer diagnosis and therapy, with the main emphasis of current research being the enhancement of photothermal conversion efficiencies. Herein, we report the facile synthesis of 2-3 nm boron quantum dots (B QDs), which demonstrated a remarkable photothermal conversion efficiency of 57% under NIR excitation. This outstanding performance can be attributed to the alteration of the electronic structure, which was a result from the distorted edge-effect induced by the unique empty orbit of B atoms in the B QDs. These results can be verified by B K-edge near edge X-ray absorption fine structure (NEXAFS), high-resolution transmission electron microscopy (HR-TEM) and density functional theory (DFT) calculations. The results demonstrate that B QDs represent a promising new and non-toxic agent for both multimodal NIR-driven cancer imaging and photothermal therapy. This work thus identifies B QDs as an exciting new and theranostic agent for cancer therapy. Furthermore, the synthetic strategy used here to synthesize the B QDs was simple and easily scalable.

Topics: Boron; HeLa Cells; Humans; Models, Molecular; Neoplasms; Photoacoustic Techniques; Photothermal Therapy; Quantum Dots; Theranostic Nanomedicine

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Carboxylic Acids; Drug Delivery Systems; Esters; Glycine; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Neoplasms; Sulfhydryl Compounds; Triazines

The potential biomedical applications of the MNPs nanohybrids coated with m-carboranylphosphinate (1-MNPs) as a theranostic biomaterial for cancer therapy were tested. The cellular uptake and toxicity profile of 1-MNPs from culture media by human brain endothelial cells (hCMEC/D3) and glioblastoma multiform A172 cell line were demonstrated. Prior to testing 1-MNPs' in vitro toxicity, studies of colloidal stability of the 1-MNPs' suspension in different culture media and temperatures were carried out. TEM images and chemical titration confirmed that 1-MNPs penetrate into cells. Additionally, to explore 1-MNPs' potential use in Boron Neutron Capture Therapy (BNCT) for treating cancer locally, the presence of the m-carboranyl coordinated with the MNPs core after uptake was proven by XPS and EELS. Importantly, thermal neutrons irradiation in BNCT reduced by 2.5 the number of cultured glioblastoma cells after 1-MNP treatment, and the systemic administration of 1-MNPs in mice was well tolerated with no major signs of toxicity.

Topics: Animals; Biocompatible Materials; Boron; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colloids; Diffusion; Endothelial Cells; Glioblastoma; Humans; Hydrodynamics; Ligands; Magnetite Nanoparticles; Mice; Neoplasms; Neutrons; Suspensions

In recent years, the nuclear reaction known as proton-boron fusion has been thoroughly investigated, because it has been proposed as a suitable agent capable of significant improvements in cancer therapy with protons. Thereby, precise knowledge about physical properties involved represents the main strategy to assess actual potential of the proposed treatment method based on proton-boron fusion. In this work, the effective reaction cross section is studied from a theoretical point of view, and a direct application to the inelastic collisions distribution provided by Monte Carlo simulations is reported, weighting the importance of the reaction in the energy deposition process, and hence providing useful insight in the localized nature of the technique.

Topics: Boron; Boron Neutron Capture Therapy; Humans; Isotopes; Neoplasms; Phantoms, Imaging; Protons

This paper presents Neutron Capture Enhanced Particle Therapy (NCEPT), a method for enhancing the radiation dose delivered to a tumour relative to surrounding healthy tissues during proton and carbon ion therapy by capturing thermal neutrons produced inside the treatment volume during irradiation. NCEPT utilises extant and in-development boron-10 and gadolinium-157-based drugs from the related field of neutron capture therapy. Using Monte Carlo simulations, we demonstrate that a typical proton or carbon ion therapy treatment plan generates an approximately uniform thermal neutron field within the target volume, centred around the beam path. The tissue concentrations of neutron capture agents required to obtain an arbitrary 10% increase in biological effective dose are estimated for realistic treatment plans, and compared to concentrations previously reported in the literature. We conclude that the proposed method is theoretically feasible, and can provide a worthwhile improvement in the dose delivered to the tumour relative to healthy tissue with readily achievable concentrations of neutron capture enhancement drugs.

Topics: Boron; Boron Neutron Capture Therapy; Computer Simulation; Dose-Response Relationship, Radiation; Feasibility Studies; Gadolinium; Heavy Ion Radiotherapy; Humans; Isotopes; Models, Biological; Monte Carlo Method; Neoplasms; Neutrons; Phantoms, Imaging; Protons; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted

The next step in the boron neutron capture therapy (BNCT) is the real time imaging of the boron concentration in healthy and tumor tissue. Monte Carlo simulations are employed to predict the detector response required to realize single-photon emission computed tomography in BNCT, but have failed to correctly resemble measured data for cadmium telluride detectors. In this study we have tested the gamma production cross-section data tables of commonly used libraries in the Monte Carlo code MCNP in comparison to measurements. The cross section data table TENDL-2008-ACE is reproducing measured data best, whilst the commonly used ENDL92 and other studied libraries do not include correct tables for the gamma production from the cadmium neutron capture reaction that is occurring inside the detector. Furthermore, we have discussed the size of the annihilation peaks of spectra obtained by cadmium telluride and germanium detectors.

Topics: Boron; Boron Neutron Capture Therapy; Cadmium Compounds; Computer Simulation; Humans; Isotopes; Monte Carlo Method; Neoplasms; Phantoms, Imaging; Radiometry; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Spectrometry, Gamma; Tellurium; Tomography, Emission-Computed, Single-Photon

The purpose of this study was to verify acquisition feasibility of a single photon emission computed tomography image using prompt gamma rays for proton boron fusion therapy (PBFT) and to confirm an enhanced therapeutic effect of PBFT by comparison with conventional proton therapy without use of boron.. Monte Carlo simulation was performed to acquire reconstructed image during PBFT. We acquired percentage depth dose (PDD) of the proton beams in a water phantom, energy spectrum of the prompt gamma rays, and tomographic images, including the boron uptake region (BUR; target). The prompt gamma ray image was reconstructed using maximum likelihood expectation maximisation (MLEM) with 64 projection raw data. To verify the reconstructed image, both an image profile and contrast analysis according to the iteration number were conducted. In addition, the physical distance between two BURs in the region of interest of each BUR was measured.. The PDD of the proton beam from the water phantom including the BURs shows more efficient than that of conventional proton therapy on tumour region. A 719keV prompt gamma ray peak was clearly observed in the prompt gamma ray energy spectrum. The prompt gamma ray image was reconstructed successfully using 64 projections. Different image profiles including two BURs were acquired from the reconstructed image according to the iteration number.. We confirmed successful acquisition of a prompt gamma ray image during PBFT. In addition, the quantitative image analysis results showed relatively good performance for further study.

Topics: Biophysical Phenomena; Boron; Computer Simulation; Feasibility Studies; Gamma Rays; Humans; Image Processing, Computer-Assisted; Monte Carlo Method; Neoplasms; Phantoms, Imaging; Proton Therapy; Tomography, Emission-Computed, Single-Photon

Maleimide-conjugating closo-dodecaborate sodium form 5c (MID) synthesized by the nucleophilic ring-opening reaction of closo-dodecaborate-1,4-dioxane complex 2 with tetrabutylammonium (TBA) azide was found to conjugate to free SH of cysteine and lysine residues in BSA under physiological conditions, forming highly boronated BSA that showed high and selective accumulation in tumor and significant tumor growth inhibition in colon 26 tumor-bearing mice subjected to thermal neutron irradiation.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Line; Cysteine; Drug Carriers; Female; Lysine; Maleimides; Mice; Mice, Inbred BALB C; Models, Molecular; Neoplasms; Serum Albumin, Bovine

Boron clusters represent a vast family of boron-rich compounds with extraordinary properties that provide the opportunity of exploitation in different areas of chemistry and biology. In addition, boron clusters are clinically used in boron neutron capture therapy (BNCT) of tumors. In this paper, a novel, in solid state (solvent free), thermal method for protein modification with boron clusters has been proposed.. The method is based on a cyclic ether ring opening in oxonium adduct of cyclic ether and a boron cluster with nucleophilic centers of the protein. Lysozyme was used as the model protein, and the physicochemical and biological properties of the obtained conjugates were characterized.. The main residues of modification were identified as arginine-128 and threonine-51. No significant changes in the secondary or tertiary structures of the protein after tethering of the boron cluster were found using mass spectrometry and circular dichroism measurements. However, some changes in the intermolecular interactions and hydrodynamic and catalytic properties were observed.. To the best of our knowledge, we have described the first example of an application of cyclic ether ring opening in the oxonium adducts of a boron cluster for protein modification. In addition, a distinctive feature of the proposed approach is performing the reaction in solid state and at elevated temperature.. The proposed methodology provides a new route to protein modification with boron clusters and extends the range of innovative molecules available for biological and medical testing.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Catalysis; Muramidase; Neoplasms

We investigated the concentrations of 23 elements in groundwater from arsenic (As) contaminated areas of Bangladesh and West Bengal, India to determine the potential human exposure to metals and metalloids. Elevated concentrations of As was found in all five study areas that exceeded the World Health Organization (WHO) guideline value of 10μg/L. The mean As concentrations in groundwater of Noakhali, Jalangi and Domkal, Dasdia Nonaghata, Deganga and Baruipur were 297μg/L, 262μg/L, 115μg/L, 161μg/L and 349μg/L, respectively. Elevated concentrations of Mn were also detected in all areas with mean concentrations were 139μg/L, 807μg/L, 341μg/L, 579μg/L and 584μg/L for Noakhali, Jalangi and Domkal, Dasdia Nonaghata, Deganga and Baruipur, respectively. Daily As intakes from drinking water for adults and the potential cancer risk for all areas was also estimated. Results suggest that mitigation activities such as water treatment should not only be focused on As but must also consider other elements including Mn, B and Ba. The groundwater used for public drinking purposes needs to be tested periodically for As and other elements to ensure the quality of drinking water is within the prescribed national guidelines.

Topics: Adult; Arsenic; Bangladesh; Boron; Drinking Water; Environmental Monitoring; Groundwater; Humans; India; Metals, Heavy; Neoplasms; Risk; Water Pollutants, Chemical

The 9Be(d,n)10B reaction was studied as an epithermal neutron source for brain tumor treatment through Boron Neutron Capture Therapy (BNCT). In BNCT, neutrons are classified according to their energies as thermal (<0.5 eV), epithermal (from 0.5 eV to 10 keV) or fast (>10 keV). For deep-seated tumors epithermal neutrons are needed. Since a fraction of the neutrons produced by this reaction are quite fast (up to 5-6 MeV, even for low-bombarding energies), an efficient beam shaping design is required. This task was carried out (1) by selecting the combinations of bombarding energy and target thickness that minimize the highest-energy neutron production; and (2) by the appropriate choice of the Beam Shaping Assembly (BSA) geometry, for each of the combinations found in (1). The BSA geometry was determined as the configuration that maximized the dose deliverable to the tumor in a 1 h treatment, within the constraints imposed by the healthy tissue dose adopted tolerance. Doses were calculated through the MCNP code. The highest dose deliverable to the tumor was found for an 8 μm target and a deuteron beam of 1.45 MeV. Tumor weighted doses ≥40 Gy can be delivered up to about 5 cm in depth, with a maximum value of 51 Gy at a depth of about 2 cm. This dose performance can be improved by relaxing the treatment time constraint and splitting the treatment into two 1-h sessions. These good treatment capabilities strengthen the prospects for a potential use of this reaction in BNCT.

Topics: Beryllium; Boron; Boron Neutron Capture Therapy; Gamma Rays; Monte Carlo Method; Neoplasms; Neutrons; Radioisotopes; Radiotherapy Dosage

New boron-containing chlorin derivatives 9 and 13 as agents for both photodynamic therapy (PDT) and boron neutron capture therapy (BNCT) of cancer were synthesized from photoprotoporphyrin IX dimethyl ester (2) and L-4-boronophenylalanine-related compounds. The in vivo biodistribution and clearance of 9 and 13 were investigated in tumor-bearing mice. The time to maximum accumulation of compound 13 in tumor tissue was one-fourth of that of compound 9, and compound 13 showed rapid clearance from normal tissues within 24h after injection. The in vivo therapeutic efficacy of PDT using 13 was evaluated by measuring tumor growth rates in tumor-bearing mice with 660 nm light-emitting diode irradiation at 3h after injection of 13. Tumor growth was significantly inhibited by PDT using 13. These results suggested that 13 might be a good candidate for both PDT and BNCT of cancer.

Topics: Animals; Antineoplastic Agents; Boron; Boron Neutron Capture Therapy; Boronic Acids; Cell Proliferation; Light; Mice; Mice, Inbred BALB C; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tissue Distribution

closo-Dodecaborate-encapsulating liposomes were developed as boron delivery vehicles for neutron capture therapy. The use of spermidinium as a counter cation of closo-dodecaborates was essential not only for the preparation of high boron content liposome solutions but also for efficient boron delivery to tumors.

Topics: Animals; Antineoplastic Agents; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Line, Tumor; Cell Survival; Female; Liposomes; Mice, Inbred BALB C; Neoplasms; Tumor Burden

Neutron capture therapy (NCT) is a promising non-invasive cancer therapy approach and some recent NCT research has focused on using compounds containing gadolinium as an alternative to currently used boron-10 considering several advantages that gadolinium offers compared to those of boron. In this study, we evaluated gadolinium-entrapped liposome compound as neutron capture therapy agent by in vivo experiment on colon-26 tumor-bearing mice. Gadolinium compound were injected intravenously via tail vein and allowed to accumulate into tumor site. Tumor samples were taken for quantitative analysis by ICP-MS at 2, 12, and 24 h after gadolinium compound injection. Highest gadolinium concentration was observed at about 2 h after gadolinium compound injection with an average of 40.3 μg/g of wet tumor tissue. We performed neutron irradiation at JRR-4 reactor facility of Japan Atomic Energy Research Institute in Tokaimura with average neutron fluence of 2×10¹² n/cm². The experimental results showed that the tumor growth suppression of gadolinium-injected irradiated group was revealed until about four times higher compared to the control group, and no significant weight loss were observed after treatment suggesting low systemic toxicity of this compound. The gadolinium-entrapped liposome will become one of the candidates for Gd delivery system on NCT.

Topics: Animals; Antineoplastic Agents; Boron; Drug Delivery Systems; Gadolinium; Japan; Liposomes; Male; Mice; Mice, Inbred BALB C; Neoplasms; Neutron Capture Therapy

Mercaptoundecahydrododecaborate (BSH)-encapsulating 10% distearoyl boron lipid (DSBL) liposomes were developed as a boron delivery vehicle for neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in addition to its encapsulated agents. BSH-encapsulating 10% DSBL liposomes have high boron content (B/P ratio: 2.6) that enables us to prepare liposome solution with 5000 ppm boron concentration. BSH-encapsulating 10% DSBL liposomes displayed excellent boron delivery efficacy to tumor: boron concentrations reached 174, 93, and 32 ppm at doses of 50, 30, and 15 mg B/kg, respectively. Magnescope was also encapsulated in the 10% DSBL liposomes and the real-time biodistribution of the Magnescope-encapsulating DSBL liposomes was measured in a living body using MRI. Significant antitumor effect was observed in mice injected with BSH-encapsulating 10% DSBL liposomes even at the dose of 15 mg B/kg; the tumor completely disappeared three weeks after thermal neutron irradiation ((1.5-1.8) × 10(12) neutrons/cm(2)). The current results enabled us to reduce the total dose of liposomes to less than one-fifth compared with that of the BSH-encapsulating liposomes without reducing the efficacy of boron neutron capture therapy (BNCT).

Topics: Animals; Borohydrides; Boron; Boron Neutron Capture Therapy; Female; Isotopes; Lipids; Liposomes; Mice; Mice, Inbred BALB C; Neoplasms; Sulfhydryl Compounds

A multivalent galactosyl carborane derivative 10 (dendritic glyco-borane, DGB) was synthesized and demonstrated as a potential cell-targeting agent in BNCT with HepG2 cells. DGB 10 improved the delivery of boron to HepG2 cells and neutron irradiation data show DGB 10 with ten-fold improvement at killing the HepG2 cells over BSH.

Topics: Boranes; Boron; Boron Neutron Capture Therapy; Dendrimers; Drug Delivery Systems; Galactose; Hep G2 Cells; Humans; Neoplasms

The fluorescence-labeled closo-dodecaborane lipid (FL-SBL) was synthesized from (S)-(+)-1,2-isopropylideneglycerol as a chiral starting material. FL-SBL was readily accumulated into the PEGylated DSPC liposomes prepared from DSPC, CH, and DSPE-PEG-OMe by the post insertion protocol. The boron concentrations and the fluorescent intensities of the FL-SBL-labeled DSPC liposomes increased with the increase of the additive FL-SBL, and the maximum emission wavelength of the liposomes appeared at 531 nm. A preliminary in vivo imaging study of tumor-bearing mice revealed that the FL-SBL-labeled DSPC liposomes were delivered to the tumor tissue but not distributed to hypoxic regions.

Topics: Animals; Boron; Boron Compounds; Drug Delivery Systems; Female; Fluorescence; Liposomes; Mice; Neoplasms; Oxadiazoles; Phosphatidylcholines; Phosphatidylethanolamines; Polyethylene Glycols; Stearates; Tissue Distribution

Core-polymerized and boron-conjugated micelles (PM micelles) were prepared by free radical copolymerization of a PEG-b-PLA block copolymer bearing an acetal group and a methacryloyl group (acetal-PEG-b-PLA-MA), with 1-(4-vinylbenzyl)-closo-carborane (VB-carborane), and the utility of these micelles as a tumor-targeted boron delivery system was investigated for boron neutron capture therapy (BNCT). Non-polymerized micelles (NPM micelles) that incorporated VB-carborane physically showed significant leakage of VB-carborane (ca. 50%) after 12 h incubation with 10% fetal bovine serum (FBS) at 37 °C. On the other hand, no leakage from the PM micelles was observed even after 48 h of incubation. To clarify the pharmacokinetics of the micelles, (125)I (radioisotope)-labeled PM and NPM micelles were administered to colon-26 tumor-bearing BALB/c mice. The (125)I-labeled PM micelles showed prolonged blood circulation (area under the concentration curve (AUC): 943.4) than the (125)I-labeled NPM micelles (AUC: 495.1), whereas tumor accumulation was similar for both types of micelles (AUC(PM micelle): 249.6, AUC(NPM micelle): 201.1). In contrast, the tumor accumulation of boron species in the PM micelles (AUC: 268.6) was 7-fold higher than the NPM micelles (AUC: 37.1), determined by ICP-AES. Thermal neutron irradiation yielded tumor growth suppression in the tumor-bearing mice treated with the PM micelles without reduction in body weight. On the basis of these data, the PM micelles represent a promising approach to the creation of boron carrier for BNCT.

Topics: Animals; Area Under Curve; Body Weight; Boron; Boron Neutron Capture Therapy; Lactates; Mice; Micelles; Neoplasms; Polyethylene Glycols; Polymerization; Spectrophotometry, Atomic; Spectroscopy, Fourier Transform Infrared; Time Factors; Tissue Distribution

Diagnosing tumors at an early stage when they are easily curable and may not require systemic chemotherapy remains a challenge to clinicians. In order to improve early cancer detection, gas filled hollow boron-doped silica particles have been developed, which can be used for ultrasound-guided breast conservation therapy. The particles are synthesized using a polystyrene template and subsequently calcinated to create hollow, rigid nanoporous microspheres. The microshells are filled with perfluoropentane vapor. Studies were performed in phantoms to optimize particle concentration, injection dose, and the ultrasound settings such as pulse frequency and mechanical index. In vitro studies have shown that these particles can be continuously imaged by US up to 48 min and their signal lifetime persisted for 5 days. These particles could potentially be given by intravenous injection and, in conjunction with contrast-enhanced ultrasound, be utilized as a screening tool to detect smaller breast cancers before they are detectible by traditional mammography.

Topics: Boron; Contrast Media; Humans; Microscopy, Electron, Scanning; Nanoparticles; Neoplasms; Silicon Dioxide; Ultrasonography

The in vitro and in vivo electrochemical detection of the reduced form of glutathione (L-γ-glutamyl-L-cysteinyl-glycine, GSH) using boron doped diamond (BDD) microelectrode for potential application in the assessment of cancerous tumors is presented. Accurate calibration curve for the determination of GSH could be obtained by the in vitro electrochemical measurements. Additionally, it was shown that it was possible to separate the detection of GSH from the oxidized form of glutathione (GSSG) using chronoamperometry measurements. In vivo GSH detection measurements have been performed in human cancer cells inoculated in immunodeficient mice. These measurements have shown that the difference of GSH level between cancerous and normal tissues can be detected. Moreover, GSH detection measurements carried out before and after X-ray irradiation have proved that it is possible to assess in vivo the decrease in GSH concentration in the tumor after a specific treatment.

Topics: Animals; Boron; Cell Line, Tumor; Diamond; Electrochemical Techniques; Glutathione; Glutathione Disulfide; Humans; Mice; Mice, Nude; Microelectrodes; Microscopy, Electron, Scanning; Neoplasms; Neoplasms, Experimental; Oxidation-Reduction; Reproducibility of Results; Sensitivity and Specificity; Transplantation, Heterologous

The presence of boron atoms has made carboranes, C(2)B(10)H(12), attractive candidates for boron neutron capture therapy. Because of their chemistry and possible conjugation with proteins, they can also be used to enhance interactions between pharmaceuticals and their targets and to increase the in vivo stability and bioavailability of compounds that are normally metabolized rapidly. Carboranes are isosteric to a rotating phenyl group, which they can substitute successfully in biologically active systems. A reverse ligand-protein docking approach was used in this work to identify binding proteins for carboranes. The screening was carried out on the drug target database PDTD that contains 1207 entries covering 841 known potential drug targets with structures taken from the Protein Data Bank. First, for validation, the protocol was applied to three crystal structures of proteins in which carborane derivatives are present. Then, the model was applied to systems for which the protein structure is available, but the binding site of carborane has not been reported. These systems were used for further validation of the protocol, while simultaneously providing new insight into the interactions between cage and protein. Finally, the screening was carried out on the database to reveal potential carborane binding targets of interest for biological and pharmacological activity. Carboranes are predicted to bind well to protease and metalloprotease enzymes. Other carborane pharmaceutical targets are also discussed, together with possible protein carriers.

Topics: Binding Sites; Boranes; Boron; Boron Neutron Capture Therapy; Chemistry, Pharmaceutical; Crystallography, X-Ray; Databases, Protein; Drug Delivery Systems; Drug Design; Drug Discovery; Enzyme Inhibitors; Humans; Ligands; Metalloproteases; Models, Chemical; Models, Molecular; Molecular Structure; Neoplasms; Pharmaceutical Preparations; Protein Binding; Stereoisomerism; Structure-Activity Relationship

Closo-dodecaborate lipid liposomes were developed as new vehicles for boron delivery system (BDS) of neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in combination with neutron irradiation. The liposomes composed of closo-dodecaborate lipids DSBL and DPBL displayed high cytotoxicity with thermal neutron irradiation. The closo-dodecaborate lipid liposomes were taken up into the cytoplasm by endocytosis without degradation of the liposomes. Boron concentration of 22.7 ppm in tumor was achieved by injection with DSBL-25% PEG liposomes at 20mg B/kg. Promising BNCT effects were observed in the mice injected with DSBL-25% PEG liposomes: the tumor growth was significantly suppressed after thermal neutron irradiation (1.8 x 10(12)neutrons/cm(2)).

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Line, Tumor; Drug Delivery Systems; Female; Lipids; Liposomes; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Neoplasms; Radiopharmaceuticals; Tissue Distribution; Tumor Burden

HeLa cells were incubated with neutron capture nuclei (boron-10 and gadolinium)-containing carbon nanoparticles, followed by irradiation of slow thermal neutron beam. Under a neutron flux of 6 x 10(11) n/cm(2) (or 10 min irradiation at a neutron flux of 1 x 10(9) n/cm(2) s), the percentages of acute cell death at 8 h after irradiation are 52, 55, and 28% for HeLa cells fed with BCo@CNPs, GdCo@CNPs, and Co@CNPs, respectively. The proliferation capability of the survived HeLa cells was also found to be significantly suppressed. At 48 h after neutron irradiation, the cell viability further decreases to 35 +/- 5% as compared to the control set receiving the same amount of neutron irradiation dose but in the absence of carbon nanoparticles. This work demonstrates "proof-of-concept" examples of neutron capture therapy using (10)B-, (157)Gd-, and (59)Co-containing carbon nanoparticles for effective destruction of cancer cells. It will also be reported the preparation and surface functionalization of boron or gadolinium doped core-shell cobalt/carbon nanoparticles (BCo@CNPs, GdCo@CNPs and Co@CNPs) using a modified DC pulsed arc discharge method, and their characterization by various spectroscopic measurements, including TEM, XRD, SQUID, FT-IR, etc. Tumor cell targeting ability was introduced by surface modification of these carbon nanoparticles with folate moieties.

Topics: Boron; Boron Neutron Capture Therapy; Carbon; Cell Survival; Cobalt; Gadolinium; HeLa Cells; Humans; Isotopes; Nanoparticles; Neoplasms; Neutron Capture Therapy

At the boron neutron capture therapy (BNCT) facility in Petten, the Netherlands, (10)B concentrations in biological materials are measured with the prompt gamma ray analyses facility that is calibrated using certified (10)B solutions ranging from 0 to 210 ppm. For this study, newly certified (10)B solutions ranging up to 1972 ppm are added. MCNP simulations of the setup range to 5000 ppm. A second order polynomial (as already used) will fit (10)B-concentrations less than 300 ppm. Above 300 ppm a fitted third order polynomial is needed to describe the calibration curve accurately.

Topics: Boron; Boron Neutron Capture Therapy; Facility Design and Construction; Gamma Rays; Humans; Isotopes; Models, Statistical; Monte Carlo Method; Neoplasms; Netherlands; Nuclear Reactors; Reference Standards; Spectrometry, Gamma; Tissue Distribution

We report on a new solid state dosimeter based on chemical vapor deposition (CVD) single crystal diamond fabricated at Roma "Tor Vergata" University laboratories. The dosimeter has been specifically designed for direct neutron dose measurements in boron neutron capture therapy (BNCT). The response to thermal neutrons of the proposed diamond dosimeter is directly due to (10)B and, therefore, the dosimeter response is directly proportional to the boron absorbed doses in BNCT. Two single crystal diamond detectors are fabricated in a p-type/intrinsic/metal configuration and are sandwiched together with a boron containing layer in between the metallic contacts (see Fig.1). Neutron irradiations were performed at the Frascati Neutron Generator (FNG) using the 2.5 MeV neutrons produced through the D(d,n)(3)He fusion reaction. Thermal neutrons were then produced by slowing down the 2.5 MeV neutrons using a cylindrical polymethylmethacrylate (PMMA) moderator. The diamond dosimeter was placed in the center of the moderator. The products of (10)B(n,alpha)Li nuclear reaction were collected simultaneously giving rise to a single peak. Stable performance, high reproducibility, high efficiency and good linearity were observed.

Topics: Boron; Boron Neutron Capture Therapy; Diamond; Equipment Design; Fast Neutrons; Humans; Isotopes; Italy; Neoplasms; Radiation-Sensitizing Agents; Radiometry; Radiotherapy Planning, Computer-Assisted

Boron neutron capture therapy has now been used for several malignancies. Most clinical trials have addressed its use for the treatment of glioblastoma multiforme. A few trials have focused on the treatment of malignant melanoma with brain metastases. Trial results for the treatment of glioblastoma multiforme have been encouraging, but have not achieved the success anticipated. Results of trials for the treatment of malignant melanoma have been very promising, though with too few patients for conclusions to be drawn. Subsequent to these trials, regimens for undifferentiated thyroid carcinoma, hepatic metastases from adenocarcinoma of the colon, and head and neck malignancies have been developed. These tumors have also responded well to boron neutron capture therapy. Glioblastoma is an infiltrative tumor with distant individual tumor cells that might create a mechanism for therapeutic failure though recurrences are often local. The microdosimetry of boron neutron capture therapy can provide an explanation for this observation. Codes written to examine the micrometer scale energy deposition in boron neutron capture therapy have been used to explore the effects of near neighbor cells. Near neighbor cells can contribute a significantly increased dose depending on the geometric relationships. Different geometries demonstrate that tumors which grow by direct extension have a greater near neighbor effect, whereas infiltrative tumors lose this near neighbor dose which can be a significant decrease in dose to the cells that do not achieve optimal boron loading. This understanding helps to explain prior trial results and implies that tumors with small, closely packed cells that grow by direct extension will be the most amenable to boron neutron capture therapy.

Topics: Boron; Boron Neutron Capture Therapy; Humans; Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Planning, Computer-Assisted; Software

This article reports on the development of a prototype of a SPECT tomograph system for online dosimetry in BNCT based on LaBr(3)(Ce) scintillation detectors. The setup shielding was optimized to be used in the accelerator based BNCT facility of the University of Birmingham. The system was designed and built. An image of a (241)Am point source was reconstructed. A projection of a phantom with two tumors with 400 microg/g of (10)B was measured at the BNCT facility.

Topics: Boron; Boron Neutron Capture Therapy; England; Equipment Design; Humans; Isotopes; Neoplasms; Phantoms, Imaging; Radiation-Sensitizing Agents; Radiotherapy Planning, Computer-Assisted; Tomography, Emission-Computed, Single-Photon

The ion transport Monte Carlo code SRIM has been used to calculate single event lineal energy spectra for the products of the boron-neutron capture reaction in a water-based medium. The event spectra have been benchmarked against spectra measured with a boron-loaded tissue-equivalent proportional counter (TEPC). Agreement is excellent and supports the use of Monte Carlo methods in understanding the influence of boron delivery on the effectiveness of boron-neutron capture therapy (BNCT).

Topics: Boron; Boron Neutron Capture Therapy; Helium; Humans; Linear Energy Transfer; Lithium; Monte Carlo Method; Neoplasms; Phantoms, Imaging; Radiation-Sensitizing Agents; Radiotherapy Planning, Computer-Assisted

Positron emission tomography (PET) has become a key imaging tool in clinical practice and biomedical research to quantify and study biochemical processes in vivo. Physiologically active compounds are tagged with positron emitters (e.g. (18)F, (11)C, (124)I) while maintaining their biological properties, and are administered intravenously in tracer amounts (10(-9)-10(-12)M quantities). The recent physical integration of PET and computed tomography (CT) in hybrid PET/CT scanners allows a combined anatomical and functional imaging: nowadays PET molecular imaging is emerging as powerful pharmacological tool in oncology, neurology and for treatment planning as guidance for radiation therapy. The in vivo pharmacokinetics of boron carrier for BNCT and the quantification of (10)B in living tissue were performed by PET in the late nineties using compartmental models based on PET data. Nowadays PET and PET/CT have been used to address the issue of pharmacokinetic, metabolism and accumulation of BPA in target tissue. The added value of the use of L-[(18)F]FBPA and PET/CT in BNCT is to provide key data on the tumour extraction of (10)B-BPA versus normal tissue and to predict the efficacy of the treatment based on a single-study patient analysis. Due to the complexity of a binary treatment like BNCT, the role of PET/CT is currently to design new criteria for patient enrolment in treatment protocols: the L-[(18)F]BPA/PET methodology could be considered as an important tool in newly designed clinical trials to better estimate the concentration ratio of BPA in the tumour as compared to neighbouring normal tissues. Based on these values for individual patients the decision could be made whether BNCT treatment could be advantageous due to a selective accumulation of BPA in an individual tumour. This approach, applicable in different tumour entities like melanoma, glioblastoma and head and neck malignancies, make this methodology as reliable prognostic and therapeutic indicator for patient undergoing BNCT.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Fluorine Radioisotopes; Humans; Isotopes; Lymphatic Metastasis; Melanoma; Models, Biological; Neoplasms; Phenylalanine; Positron-Emission Tomography; Prognosis; Radiation-Sensitizing Agents; Tomography, X-Ray Computed

Water-soluble carborane functionalized nanoparticles also co-functionalized with targeting antibodies have been prepared. We demonstrate tumour cell targeting with anti-EGFR antibodies and delivery of a high concentration of boron using SERS imaging. This suggests these materials have a therapeutic potential in addition to multimodal imaging capabilities.

Topics: Antibodies, Neoplasm; Boron; Cell Line, Tumor; Drug Delivery Systems; ErbB Receptors; Humans; Nanoparticles; Neoplasms; Spectrum Analysis, Raman

The ability to selectively hit the tumour cells is an essential characteristic of an anti-tumour therapy. In boron neutron capture therapy (BNCT) this characteristic is based on the selective uptake of (10)B in the tumour cells with respect to normal tissues. An important step in the BNCT planning is the measurement of the boron concentration in the tissue samples, both tumour and healthy. When the tumour is spread through the healthy tissue, as in the case of metastases, the knowledge of the different kinds of tissues in the sample being analysed is crucial. If the percentage of tumour and normal tissues cannot be evaluated, the obtained concentration is a mean value depending on the composition of the different samples being measured. In this case an imaging method that could give information both on the morphology and on the spatial distribution of boron concentration in the sample would be a fundamental support. In this paper, the results of the boron uptake analysis in the tumour and in the healthy samples taken from human livers after boron phenylalanine (BPA) infusion are shown; boron imaging was performed using neutron autoradiography.

Topics: Autoradiography; Boron; Humans; Neoplasm Metastasis; Neoplasms; Neutrons; Radionuclide Imaging; Tissue Distribution

The meaningful sharing and combining of clinical results from different centers in the world performing boron neutron capture therapy (BNCT) requires improved precision in dose specification between programs. To this end absorbed dose normalizations were performed for the European clinical centers at the Joint Research Centre of the European Commission, Petten (The Netherlands), Nuclear Research Institute, Rez (Czech Republic), VTT, Espoo (Finland), and Studsvik, Nyköping (Sweden). Each European group prepared a treatment plan calculation that was bench-marked against Massachusetts Institute of Technology (MIT) dosimetry performed in a large, water-filled phantom to uniformly evaluate dose specifications with an estimated precision of +/-2%-3%. These normalizations were compared with those derived from an earlier exchange between Brookhaven National Laboratory (BNL) and MIT in the USA. Neglecting the uncertainties related to biological weighting factors, large variations between calculated and measured dose are apparent that depend upon the 10B uptake in tissue. Assuming a boron concentration of 15 microg g(-1) in normal tissue, differences in the evaluated maximum dose to brain for the same nominal specification of 10 Gy(w) at the different facilities range between 7.6 and 13.2 Gy(w) in the trials using boronophenylalanine (BPA) as the boron delivery compound and between 8.9 and 11.1 Gy(w) in the two boron sulfhydryl (BSH) studies. Most notably, the value for the same specified dose of 10 Gy(w) determined at the different participating centers using BPA is significantly higher than at BNL by 32% (MIT), 43% (VTT), 49% (JRC), and 74% (Studsvik). Conversion of dose specification is now possible between all active participants and should be incorporated into future multi-center patient analyses.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Clinical Trials as Topic; Humans; Isotopes; Neoplasms; Phantoms, Imaging; Phenylalanine; Radiation-Sensitizing Agents; Radiometry; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Reproducibility of Results; Software; Treatment Outcome

The use of neutrons in radiotherapy allows the possibility of producing nuclear reactions in a specific target inserted in the medium. (10)B is being used to induce reactions (n, alpha), a technique called boron neutron capture therapy. I have studied the possibility of inducing a similar reaction using the nucleus of (33)S, for which the reaction cross section presents resonances for keV neutrons, the highest peak occurring at 13.5 keV. Here shown, by means of Monte Carlo simulation of point-like sources of neutrons in this energy range, is an enhancement effect on the absorbed dose in water by the addition of (33)S atoms. In addition to this, as the range of the alpha particle is of the order of a mammalian cell size, the energy deposition via this reaction results mainly inside the cells adjacent to the interaction site. The main conclusion of the present work is that the insertion of these sulphur atoms in tumoral cells would enhance the effect of neutron irradiation in the keV range.

Topics: Algorithms; Animals; Biophysics; Boron; Boron Neutron Capture Therapy; Computer Simulation; Humans; Isotopes; Models, Statistical; Monte Carlo Method; Neoplasms; Neutrons; Radiotherapy; Sulfur Isotopes; Water

Two new HA derivatives bearing carborane rings were synthesized by click chemistry. The optimal conditions were assessed for the preparation of biocompatible boron carriers, potentially suitable for application in BNCT and capable of targeting the CD44 antigen. The new polymeric samples were characterized by means of NMR-spectroscopy techniques that gave degrees of 17 and 8% for HAAACB and HapACB, respectively. Both HAAACB and HApACB turned out to be nontoxic for colorectal, ovarian and bladder tumor cell lines, to disclose a specific interaction with the CD44 antigen as the native hyaluronan moiety, and to deliver boron-atom concentrations largely sufficient for BNCT therapy when accumulated in cancer cells.

Topics: Boron; Cell Line, Tumor; Drug Delivery Systems; Humans; Hyaluronan Receptors; Hyaluronic Acid; Magnetic Resonance Spectroscopy; Neoplasms; Trace Elements

Magnetic resonance imaging (MRI) and boron-neutron capture therapy (BNCT) are quite attractive techniques for diagnosis and treatment of cancer, respectively. In order to progress the study on both MRI and BNCT, the novel compounds containing 19F and 10B atoms in a single molecule were designed and synthesized. In the present paper, the syntheses and the internalization rates into tumor cells of these compounds are elucidated.

Topics: Animals; Boron; Boron Neutron Capture Therapy; Boronic Acids; Cell Line, Tumor; Cells, Cultured; Contrast Media; Fluorine; HeLa Cells; Humans; Isotopes; Magnetic Resonance Imaging; Molecular Structure; Neoplasms; Phenylalanine; Rats

A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available neutron irradiation treatment facilities are examined for this application. The tumour boron concentrations and tumour to healthy tissue concentration ratios required to deliver 50 Gy-Eq to the tumour without exceeding 18 Gy-Eq in the skin are determined, as well as the associated therapeutic ratios. Discussion is provided to address the future research direction for assessing the feasibility of the proposed concept.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boron; Boron Neutron Capture Therapy; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Hot Temperature; Humans; Models, Biological; Models, Theoretical; Monte Carlo Method; Neoplasm Metastasis; Neoplasms; Neutrons; Radiotherapy Dosage; Receptor, ErbB-2; Software; Trastuzumab

A number of azanonaboranes containing imidazole derivatives have been synthesized by a ligand-exchange reaction. The exo-NH(2)R group of the azanonaborane of the type [(RH(2)N)B(8)H(11)NHR] can be exchanged by one hetero-nitrogen atom of the imidazole ring. In the case of histamine, the exchange takes place on the aliphatic amino group, the hetero-nitrogen atom of the imidazole ring or both of them. The products were confirmed by NMR, IR spectroscopy, elemental analysis, and mass spectrometry. The electron-withdrawing effect of the nitro group in 2-nitroimidazole is the main hindrance to achieve the exchange reaction. In vitro experiments were performed with B16 melanoma cells. A comparison of the biological properties of the products in which the B(8)N cluster is connected to the hetero-nitrogen atom of imidazole ring or the aliphatic NH(2) group showed that incorporation of B(8)N cluster unit into primary amino group increases the compound's toxicity. In contrast, this specificity for cytotoxicity effect was not observed in the case of histamine containing two B(8)N clusters which was relatively nontoxic and did not inhibit colony formation up to concentrations of 2 mM.

Topics: Animals; Aza Compounds; Boranes; Boron; Imidazoles; Melanoma, Experimental; Neoplasms; Neutrons; Radiotherapy; Tumor Cells, Cultured

The successful treatment of cancer by boron neutron-capture therapy (BNCT) requires the selective delivery of relatively high concentration of 10B compounds to malignant tumor tissue. This study focuses on a new tumor-targeting drug delivery system for BNCT that uses small (less than 200 nm in diameter), unilamellar mercaptoundecahydrododecaborate (BSH)-encapsulating, transferrin (TF)-conjugated polyethyleneglycol liposomes (TF-PEG liposomes). When TF-PEG liposomes were injected at a dose of 35 mg 10B/kg, we observed a prolonged residence time in the circulation and low uptake by the reticuloendothelial system (RES) in Colon 26 tumor-bearing mice, resulting in enhanced accumulation of 10B into the solid tumor tissue (e.g., 35.5 microg/g). TF-PEG liposomes maintained a high 10B level in the tumor, with concentrations over 30 microg/g for at least 72 h after injection. This high retention of 10B in tumor tissue indicates that binding and concomitant cellular uptake of the extravasated TF-PEG liposomes occurs by TF receptor and receptor-mediated endocytosis, respectively. On the other hand, the plasma level of 10B decreased, resulting in a tumor/plasma ratio of 6.0 at 72 h after injection. Therefore, 72 h after injection of TF-PEG liposomes was selected as the time point of BNCT treatment. Administration of BSH encapsulated in TF-PEG liposomes at a dose of 5 or 20 mg 10B/kg and irradiation with 2 x 10(12) neutrons/cm2 for 37 min produced tumor growth suppression and improved long-term survival compared with PEG liposomes, bare liposomes and free BSH. Thus, intravenous injection of TF-PEG liposomes can increase the tumor retention of 10B atoms, which were introduced by receptor-mediated endocytosis of liposomes after binding, causing tumor growth suppression in vivo upon thermal neutron irradiation. These results suggest that BSH-encapsulating TF-PEG liposomes may be useful as a new intracellular targeting carrier in BNCT therapy for cancer.

Topics: Animals; Area Under Curve; Borohydrides; Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Endocytosis; Isotopes; Liposomes; Liver; Male; Mice; Mice, Inbred BALB C; Neoplasms; Neutrons; Particle Size; Polyethylene Glycols; Sulfhydryl Compounds; Survival Rate; Tissue Distribution; Transferrin

The blood boron concentration regulates directly the BNCT irradiation time in which the prescribed dose to the patient is delivered. Therefore a proper estimation of the blood boron concentration for the treatment field based on the measured blood samples before irradiation is required. The bi-exponential model fit using Levenberg-Marquardt method was implemented for this purpose to provide the blood boron concentration estimates directly to the treatment data flow during the BNCT procedure. The harmonic mean bi-exponential decay half-lives of the studied patient data (n=28) were 15+/-8 and 320+/-70 min for the faster and slower half-life. The model uncertainty (n=28) was reasonably low, 0.7+/-0.1 microg/g (about 5%). The implemented algorithm provides a robust method for temporal blood boron concentration estimation for BPA-F mediated BNCT. Utilization of the infusion data improves the reliability of the estimate. The overall data flow during the treatment fulfills the practical requirements concerning the BNCT procedure.

Topics: Algorithms; Boron; Boron Compounds; Boron Neutron Capture Therapy; Finland; Fructose; Half-Life; Humans; Models, Biological; Neoplasms

The characteristics boron-dose enhancer (BDE) was evaluated as to the dependence on the (10)B concentration for BNCT using near-threshold (7)Li(p,n)(7)Be direct neutrons. The treatable protocol depth (TPD) was utilized as an evaluation index. MCNP-4B calculations were performed for near-threshold (7)Li(p,n)(7)Be at a proton energy of 1.900MeV and for a polyethylene BDE. Consequently, the TPD was increased by increasing T/N ratio, i.e., the ratio of the (10)B concentration in the tumor ((10)B(Tumor)) to that in the normal tissue ((10)B(Normal)), and by increasing (10)B(Tumor) and (10)B(Normal) for constant T/N ratio. It has been found that the BDE becomes unnecessary from the viewpoint of increasing the TPD, when (10)B(Tumor) is over a certain level.

Topics: Beryllium; Boron; Boron Neutron Capture Therapy; Fast Neutrons; Humans; Japan; Lithium; Neoplasms; Phantoms, Imaging; Radioisotopes; Radiotherapy Planning, Computer-Assisted

The idea to couple the treatment planning system (TPS) to the information on the real boron distribution in the patient acquired by positron emission tomography (PET) is the main added value of the new methodology set-up at DIMNP (Dipartimento di Ingegneria Meccanica, Nucleare e della Produzione) of University of Pisa, in collaboration with the JRC (Joint Research Centre) at Petten (NL). This methodology has been implemented in a new TPS, called Boron Distribution Treatment Planning System (BDTPS), which takes into account the actual boron distribution in the patient's organ, as opposed to other TPSs used in BNCT that assume an ideal uniform boron distribution. BDTPS is based on the Monte Carlo technique and has been experimentally validated comparing the computed main parameters (thermal neutron flux, boron dose, etc.) to those measured during the irradiation of an ad hoc designed phantom (HEterogeneous BOron phantoM, HEBOM). The results are also in good agreement with those obtained by the standard TPS SERA and by reference calculations carried out using an analytical model with the MCNP code. In this paper, the methodology followed for both the experimental and the computational validation of BDTPS is described.

Topics: Boron; Boron Neutron Capture Therapy; Humans; Monte Carlo Method; Neoplasms; Phantoms, Imaging; Positron-Emission Tomography; Radiotherapy Planning, Computer-Assisted

The aim of our work is to target (10)B to the tumor vasculature for neutron capture therapy (NCT). Alpha (v)-integrin specific RGD-peptides were coupled to liposomes that encapsulated dodecahydrododecaborate. These RGD-liposomes strongly associated with human umbilical vein endothelial cells (HUVEC) expressing this integrin and were internalized. Proliferating HUVEC proved sensitive to treatment with gamma-irradiation resulting in decreased cell viability and pronounced inhibition of DNA-synthesis with increasing dose. Irradiation of RGD-(10)B-liposome incubated HUVEC with neutrons strongly inhibited endothelial cell viability. These results suggest that efficient NCT can be achieved by targeting (10)B-liposomes to angiogenic endothelium in tumors.

Topics: Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Cell Survival; Cells, Cultured; DNA, Neoplasm; Endothelium, Vascular; Gamma Rays; Humans; Isotopes; Liposomes; Neoplasms; Neovascularization, Pathologic; Oligopeptides

Recently, various boronated porphyrins have been shown to preferentially target a variety of tumour types. Of the different porphyrins evaluated, copper tetra-phenyl-carboranyl porphyrin (CuTCPH) is a strong candidate for future preclinical evaluation. In the present study, the responses of two critical normal tissues, skin and central nervous system (CNS), to boron neutron capture (BNC) irradiation in the presence of this porphyrin were evaluated.. Standard models for the skin and spinal cord of adult male Fischer 344 rats were used. CuTCPH was administered by intravenous infusion at a dose of 200 mg x kg(-1) body weight, over 48 h. The thermal beam at the Brookhaven Medical Research Reactor was used for the BNC irradiations. The 20-mm diameter irradiation field, for both the skin and the spinal cord, was located on the mid-dorsal line of the neck. Dose-response data were fitted using probit analysis and the doses required to produce a 50% incidence rate of early and late skin changes or myeloparesis (ED(50) +/- SE) were calculated from these curves.. Biodistribution studies indicated very low levels of boron (<3 microg x g(-1)) in the blood 3 days after the administration of CuTCPH. This was the time point selected for radiation exposure in the radiobiological studies. Levels of boron in the CNS were also low (2.8 +/- 0.6 microg x g(-1)) after 3 days. However, the concentration of boron in the skin was considerably higher at 22.7 +/- 2.6 microg x g(-1). Single radiation exposures were carried out using a thermal neutron beam. The impact of CuTCPH-mediated BNC irradiation on the normal skin and CNS at therapeutically effective exposure times was minimal. This was primarily due to the very low blood boron levels (from CuTCPH) at the time of irradiation. Analysis of the relevant dose-effect data gave compound biological effectiveness factors of about 1.8 for skin (moist desquamation) and about 4.4 for spinal cord (myeloparesis) for CuTCPH. These values were based on the BNC radiation doses to tissues calculated using the blood boron levels at the time of irradiation.. CuTCPH-mediated BNC irradiation will not cause significant damage to skin and CNS at clinically relevant radiation doses provided that blood boron levels are low at the time of radiation exposure.

Topics: Animals; Boron; Boron Neutron Capture Therapy; Central Nervous System; Dose-Response Relationship, Radiation; Neoplasms; Porphyrins; Radiation Injuries, Experimental; Radiometry; Rats; Rats, Inbred F344; Skin; Time Factors

The goal of the present study was to investigate HER-2-targeted boron-containing liposomes as a potential drug delivery vehicle for boron neutron capture therapy (BNCT). Trastuzumab was conjugated to the distal end of PEG-DSPE-NHS in micelles and the Trastuzumab-PEG-DSPE were then transferred to preformed liposomes, either empty or loaded with water soluble boronated acridine (WSA), using the micelle transfer method. The final conjugates were referred to as Trastuzumab-liposome and Trastuzumab-liposome-WSA. The binding specificity, uptake, retention and internalization of Trastuzumab-liposome-WSA conjugates were studied in cultured SK-BR-3 cells, with regard to the targeting agent, carrier, and the load. The subcellular location of WSA was studied using confocal microscopy. The conjugates showed specific binding to the HER-2 receptors of SK-BR-3 cells. High cellular uptake and internalization of the conjugates was seen, reaching 132 ppm of boron in the targeted cells after 24 h. WSA was distributed mainly in the cytoplasm and was shown to have long cellular retention, with 90% and 67% of the boron remained in the cells after 24 h and 48 h, respectively. The conjugate Trastuzumab-liposome-WSA could be considered as a potent drug delivery system for BNCT.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Cell Membrane; Drug Delivery Systems; Humans; Liposomes; Micelles; Microscopy, Fluorescence; Neoplasms; Protein Binding; Time Factors; Trastuzumab

Polyamine vectors are attractive for tumor targeting. We envisaged (Z)-1,4-diamino-2-butene (Z-DAB), an unsaturated analogue of putrescine as vector of (10)B, (18)F and (131)I for boron neutron capture therapy (BNCT), and tumor imaging by positron emission tomography or scintigraphy respectively. In the present work, the synthesis and characterization of new derivatives of Z-DAB were reported. Z-DAB was actively transported in cells via the polyamine transport system and converted into the spermidine analogue.(E)-2-iodo-1,4-diamino-2-butene (E-I-DAB) was not taken up by the polyamine transport system and may not be suitable for tumor imaging. In contrast, (Z)-2-[4-(5,5-dimethyl-dioxaborinan-2-yl)phenyl]methyl-1,4-diamino-2-butene (Z-4-Bbz-DAB) was a substrate of the transport system and allowed significant boron accumulation in 3LL cells. Its potential in BNCT will be evaluated.

Topics: Animals; Biological Transport; Boron; Cell Division; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Fluorine Radioisotopes; Halogens; Humans; Iodine Radioisotopes; Neoplasms; Polyamines; Putrescine; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Tumor Cells, Cultured

Boron neutron capture therapy (BNCT), an experimental treatment for certain cancers, destroys only cells near the boron; however, there is a need to develop highly specific delivery agents. As nucleic acid aptamers recognize specific molecular targets, we investigated the influence of boronated nucleotide analogs on RNA function and on the systematic evolution of ligands by exponential enrichment (SELEX) process. Substitution of guanosine 5'-(alpha-P-borano) triphosphate (bG) for GTP or uridine 5'-(alpha-P-borano) triphosphate (bU) for UTP in several known aptamers diminished or eliminated target recognition by those RNAs. Specifically, ATP-binding aptamers containing the zeta-fold, which appears in several selections for adenosine aptamers, became inactive upon bG substitution but were only moderately affected by bU substitution. Selections were carried out using the bG or bU analogs with C8-linked ATP agarose as the binding target. The selections with bU and normal NTP yielded some zeta-fold aptamers, while the bG selection yielded none of this type. Non-zeta aptamers from bU and bG populations tolerated the borano substitution and many required it. The borano nucleotide requirement is specific; bU could not be used in bG-dependent aptamers nor vice versa. The borano group plays an essential role, as yet undefined, in target recognition or RNA structure. We conclude that the bG and bU nucleotides are fully compatible with SELEX, and that these analogs could be used to make boronated aptamers as therapeutics for BNCT.

Topics: Adenosine Triphosphate; Base Sequence; Binding Sites; Boron; Boron Neutron Capture Therapy; Directed Molecular Evolution; Molecular Sequence Data; Neoplasms; Nucleic Acid Conformation; Oligoribonucleotides; Sequence Alignment

Boron neutron capture therapy (BNCT) is a radiation therapy in which the neutron capture reaction of 10B is used for the selective destruction of tumours. At the High Flux Reactor (HFR) in Petten, a therapy facility with an epithermal neutron beam has been built. In the first instance, patients with brain tumours will be treated. The doses delivered to the tumour and to the healthy tissue depend on the thermal neutron fluence and on the boron concentrations in these regions. An accurate determination of the patient dose during therapy requires knowledge of these time-dependent concentrations. For this reason, a gamma-ray telescope system, together with a reconstruction formalism, have been developed. By using a gamma-ray detector in a telescope configuration, boron neutron capture gamma-rays of 478 keV emitted by a small specific region can be detected. The reconstruction formalism can calculate absolute boron concentrations using the measured boron gamma-ray detection rates. Besides the boron gamma-rays, a large component of 2.2 MeV gamma-rays emitted at thermal neutron capture in hydrogen is measured. Since the hydrogen distribution is almost homogeneous within the head, this component can serve as a measure of the total number of thermal neutrons in the observed volume. By using the hydrogen gamma-ray detection rate for normalization of the boron concentration, the reconstruction tool eliminates the greater part of the influence of the inhomogeneity of the thermal neutron distribution. MCNP calculations are used as a tool for the optimization of the detector configuration. Experiments on a head phantom with 5 ppm 10B in healthy tissue showed that boron detection with a standard deviation of 3% requires a minimum measuring time of 2 min live time. From two position-dependent measurements, boron concentrations in two compartments (healthy tissue and tumour) can be determined. The reconstruction of the boron concentration in healthy tissue can be done with a standard deviation of 6%. The gamma-ray telescope can also be used for in vivo dosimetry.

Topics: Boron; Boron Neutron Capture Therapy; Equipment Design; Gamma Rays; Head; Humans; Image Processing, Computer-Assisted; Neoplasms; Neutrons; Online Systems; Phantoms, Imaging; Radiotherapy Dosage

In boron neutron capture therapy (BNCT) the absorbed dose to the tumor cells and healthy tissues depends critically on the boron uptake. Pronounced individual variations in the uptake patterns have been observed for two boron compounds currently used in clinical trials. This implies a high uncertainty in the determination of the boron dose component. In the present work a technique known as prompt gamma spectroscopy (PGS) is studied that potentially can be used for in vivo and noninvasive boron concentration determination at the time of the treatment. The technique is based upon measurement of gamma rays promptly emitted in the 10B(n,alpha)7Li and 1H(n,gamma)2D reactions. The aim of this work is to prepare the present setup for clinical application as a monitor of boron uptake in BNCT patients. Therefore, a full calibration and a set of phantom experiments were performed in a clinical setting. Specifically, a nonuniform boron distribution was studied; a skin/ dura, a larger blood vessel, and tumor within a head phantom was simulated. The results show that it is possible to determine a homogeneous boron concentration of 5 microg/g within +/-3% (1 standard deviation). In the nonuniform case, this work shows that the boron concentration can be determined through a multistep measurement procedure, however, with a somewhat higher uncertainty (approximately 10%). The present work forms the basis for a subsequent clinical application of the PGS setup aimed at in vivo monitoring of boron uptake.

Topics: Blood Vessels; Boron; Boron Neutron Capture Therapy; Brain; Calibration; Humans; Models, Statistical; Neoplasms; Neutrons; Phantoms, Imaging; Spectrometry, Gamma

Topics: Boron; Humans; Neoplasms; Neutron Capture Therapy; Radioisotopes

Topics: Animals; Boron; Brachytherapy; Humans; Neoplasms; Neutrons; Rats

Topics: Boron; Brachytherapy; Californium; Humans; Neoplasms; Neutrons; Radioisotope Teletherapy

Preclinical studies for boron neutron capture therapy (BNCT) using epithermal neutrons are ongoing at several laboratories. The absorbed dose in tumor cells is a function of the thermal neutron flux at depth, the microscopic boron concentration, and the size of the cell. Dosimetry is therefore complicated by the admixture of thermal, epithermal, and fast neutrons, plus gamma rays, and the array of secondary high-linear-energy-transfer particles produced within the patient from neutron interactions. Microdosimetry can be a viable technique for determining absorbed dose and radiation quality. A 2.5-cm-diameter tissue-equivalent gas proportional counter has been built with 50 parts per million (ppm) 10B incorporated into the walls and counting gas to simulate the boron uptake anticipated in tumors. Measurements of lineal energy (y) spectra for BNCT in simulated volumes of 1-10 microns diameter show a dose enhancement factor of 4.3 for 30 ppm boron, and a "y" of 250 keV/microns for the boron capture process. Chamber design plus details of experimental and calculated linear energy spectra will be presented.

Topics: Boron; Humans; Isotopes; Models, Structural; Neoplasms; Neutrons; Radiometry; Radiotherapy, High-Energy

A Monte Carlo simulation study has been carried out to investigate the suitability of neutron beams of various energies for therapeutic efficacy in boron neutron capture therapy. The dosimetric properties of unidirectional, monoenergetic neutron beams of varying diameters in two different phantoms (a right-circular cylinder and an ellipsoid) made of brain-equivalent material were examined. The source diameter was varied from 0.0 to 20.0 cm; neutron energies ranged from 0.025 eV up to 800 keV, the maximum neutron energy generated by a tandem cascade accelerator using 2.5-MeV protons in a 7Li(p,n)7Be reaction. Such a device is currently under investigation for use as a neutron source for boron neutron capture therapy. The simulation studies indicate that the maximum effective treatment depth (advantage depth) in the brain is 10.0 cm and is obtainable with a 10-keV neutron beam. A useful range of energies, defined as those neutron energies capable of effectively treating to a depth of 7 cm in brain tissue, is found to be 4.0 eV to 40.0 keV. Beam size is shown not to affect advantage depth as long as the entire phantom volume is used in determining this depth. Dose distribution in directions parallel to and perpendicular to the beam direction are shown to illustrate this phenomenon graphically as well as to illustrate the differences in advantage depth and advantage ratio and the contribution of individual dose components to tumor dose caused by the geometric differences in phantom shape.

Topics: Boron; Brain Neoplasms; Computer Simulation; Humans; Isotopes; Models, Structural; Monte Carlo Method; Neoplasms; Neutrons; Radiotherapy Dosage

In order to determine 10B concentrations in a tumour in vivo without injuring tissues, phantom experiments and calculations were carried out for boron neutron capture therapy. The experiment was based on prompt gamma ray spectroscopy and a single-crystal silicon-filtered neutron beam from a TRIGA-II reactor. Calibration curves to determine the 10B concentrations in the tumours were experimentally generated from known 10B values for simulated tumours with various volumes in a phantom. The 10B distributions in a tumour were also investigated and it was possible to distinguish the tumour with 10B from normal tissue without 10B. In addition, the 10B concentrations were estimated by calculations. A two-dimensional discrete ordinate transport code, DOT3.5, was employed for the calculations of the neutron fluence rate distributions in a phantom. The number of incidental gamma rays entering a germanium detector, which were produced in a tumour as a result of neutron reaction, were calculated by an analytical method. The results were in good agreement with the experiments.

Topics: Boron; Gamma Rays; Humans; Isotopes; Models, Anatomic; Neoplasms; Spectrum Analysis

Distributions of thermal neutron fluence and capture gamma ray absorbed dose rates were evaluated, taking into consideration various physical factors relevant to boron neutron capture therapy. The use of a larger neutron irradiation aperture was associated with an increase in thermal neutron fluence and capture gamma ray absorbed dose rates. Radiation leakage was more significant with smaller phantoms. Attenuation of thermal neutron fluence rates by 10B suggested that there was an optimal 10B concentration (less than 100 PPM) for a given tumour. Deuteration of water allowed better penetration of thermal neutrons with less capture gamma rays and is potentially applicable for the treatment of deep-seated brain tumours.

Topics: Boron; Humans; Isotopes; Models, Biological; Models, Structural; Neoplasms; Neutrons; Radiotherapy Dosage; Radiotherapy, High-Energy

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Boron; Boron Compounds; Brain Neoplasms; Glioblastoma; Humans; Immunotoxins; Isotopes; Melanoma; Mice; Neoplasms; Neutrons; Phenylalanine; Radiation Dosage

Topics: Boron; Humans; Neoplasms; Neutrons; Radiotherapy, High-Energy

Topics: Animals; Boron; Boron Compounds; Humans; Neoplasms; Neutrons

Topics: Boron; Boron Compounds; Humans; Isotopes; Neoplasms; Neutrons; Radiotherapy; Radiotherapy Dosage

Topics: Boron; Humans; Neoplasms; Neutrons; Radiation Tolerance; Radiotherapy; Radiotherapy Dosage

Two samples of 2-phenyl-1,2-dicarba-closo-[1-3H]dodecaborane(12) were prepared by treating 1-lithio-2-phenyl-1,2-dicarba-closo-dodecaborane(12) with 3H2O (0.1 and 5.0 Ci/ml, respectively). These tritiated phenylcarborane samples were subsequently converted to corresponding samples of p-[1,2-dicarba-closo-[1-3H]dodecaboran(12)-2-yl]benzenediazonium ion ([3H]DBD) suitable for azo-coupling reactions. Reaction of the two tritiated diazonium ion samples with 2-napthol resulted in the formation of an azo dye (epsilon = 1.98 X 10(4) M-1 cm-1 at 485 nm). Experiments relating absorbance to 3H activity proved the two [3H]DBD sources to have 3.81 X 10(11) and 2.45 X 10(13) cpm of 3H per mol of tritiated carborane substituent. Purified antibodies to carcinoembryonic antigen were coupled to the [3H]DBD and, after extensive dialysis, the average number of carborane moieties per antibody molecule was determined by measuring the 3H activity associated with a known protein concentration. Further examination of these tritiated carborane-labeled antibodies by affinity chromatography proved that boron labeling did not destroy their immunoreactivity. Correlations of azo-coupling conditions (reactant ratios, pH) with immunoreactivity and antibody protein recovery are presented.

Topics: Antibodies, Neoplasm; Boron; Carcinoembryonic Antigen; Humans; Neoplasms; Neutrons

Topics: Boron; Cell Nucleus; Computers; Energy Transfer; Humans; Isotopes; Mathematics; Models, Biological; Neoplasms; Neutrons; Radiation Dosage; Radiotherapy

B-decachloro-o-carborane derivatives in which one of the carbon atoms was substituted by -CH2CH2CO2H (I), -CH2CHOHCH2-O-CH2CH=CH2 (II) and -CH2CHOHCH2-O-p-C6H4NHCOOC(CH3)3 (III) were prepared from decachloro-o-carborane and the corresponding bromo (I) or epoxi (II and III) derivatives under alkaline conditions. II could be epoxidized and bound to dextran, Concanavalin A, and human IgG, with a boron content of 4.3, 4.8, and 4.9% (w/w), respectively. III could be converted to the corresponding amine and further to the isothiocyanate. Such boron derivatives could be suitable compounds for neutron capture therapy of tumors, as they are well water soluble and could be attached to tumor specific antibodies.

Topics: Boranes; Boron; Boron Compounds; Chemical Phenomena; Chemistry; Humans; Neoplasms; Neutrons; Radioisotopes

Incorporation of 10B in tumours treated by fast-neutron therapy would increase the tumour dose via the reaction 10B(n, alpha)7Li which occurs with partially thermalised neutrons. The extent of the dose enhancement was measured for neutron beams with median energies of 2.4, 3.3, 7.0 and 9.0 MeV by two techniques: with a BF3 proportional counter in three beams and activation of 23Na in the fourth. The results obtained with the two techniques are in good agreement. The magnitude of the dose enhancement depends upon the depth, field size and neutron beam energy. The dose enhancement at a depth of 8 cm varied from 0.32% with the lowest-energy beam to 0.07% with the highest-energy beam for each microgram of 10B uptake per gram of tissue. The products of the reaction in 10B would, however, have an RBE about twice that of the fast-neutron dose in the absence of boron. The method may be useful if drugs providing adequate uptake of 10B can be synthesised.

Topics: Beryllium; Boron; Fast Neutrons; Humans; Isotopes; Lithium; Neoplasms; Neutrons; Radiotherapy, High-Energy; Relative Biological Effectiveness

Topics: Animals; Antibodies, Neoplasm; Antigen-Antibody Reactions; Antigens, Neoplasm; Antineoplastic Agents; Boron; Carcinoma, Ehrlich Tumor; Chlorambucil; Cricetinae; Cytotoxicity Tests, Immunologic; Diphtheria Toxin; Glucose Oxidase; Immune Sera; Immunotherapy; Iodine Radioisotopes; Leukemia L1210; Lymphoma; Methotrexate; Mice; Neoplasms; Neoplasms, Experimental; Rabbits

Topics: Animals; Antibodies; Antibody Specificity; Antigen-Antibody Reactions; Boranes; Boron; Cattle; Diazonium Compounds; Histocompatibility; Humans; Immune Sera; Lymphocytes; Mice; Neoplasms; Neutrons; Rabbits; Radiation Effects; Serum Albumin, Bovine; Species Specificity

Topics: Boron; Neoplasms; Neutrons; Technology, Radiologic

Topics: Boron; Cell Line; Cells, Cultured; Conjunctiva; Endoplasmic Reticulum; Female; HeLa Cells; Humans; Leukemia, Myeloid; Lung; Microscopy, Fluorescence; Neoplasms; Tetracycline; Uterine Cervical Neoplasms

Topics: Animals; Borates; Boron; Brain Chemistry; Femur; Kidney; Liver; Mice; Muscles; Neoplasms; Neoplasms, Experimental; Rats; Time Factors

Topics: Animals; Autoradiography; Boron; Colloids; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Mice; Neoplasms; Neutrons

Topics: Boron; Neoplasms; Neutrons; Radioisotopes; Radiotherapy Dosage; Radiotherapy, High-Energy

Topics: Anti-Infective Agents; Anti-Infective Agents, Local; Antimony; Arsenicals; Boron; Diuretics; Drug Therapy; Mercury Compounds; Metals; Neoplasms; Organomercury Compounds; Pharmacology; Radioisotopes; Selenium; Toxicology

Topics: Autoradiography; Boron; Mice; Microscopy; Neoplasms; Neoplasms, Experimental; Research; Tritium; Water

Topics: Acetates; Alcohols; Animals; Antineoplastic Agents; Boron; Chemistry, Pharmaceutical; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Propionates; Radiation Effects; Research; Succinates; Sulfhydryl Compounds; Water

Topics: Animals; Boron; Boronic Acids; Brain; Brain Neoplasms; Mice; Neoplasms; Neurochemistry

Topics: Animals; Boron; Brain; Brain Neoplasms; Mice; Neoplasms

Topics: Boron; Boron Compounds; Brain; Brain Neoplasms; Humans; Neoplasms; Neutron Capture Therapy; Neutrons; Tissue Distribution

Topics: Boron; Brain Neoplasms; Humans; Isotopes; Neoplasms; Neutrons; Skull

Topics: Boron; Brain; Brain Neoplasms; Humans; Neoplasms; Neutrons; Radioactivity; Radioisotopes; Skull

Topics: Boron; Boron Compounds; Humans; Neoplasms