Boron Neutron Capture Synovectomy Research Articles

Synthesis, Molecular Docking, and In Vitro Boron Neutron Capture Therapy Assay of Carboranyl Sinomenine.

In comparison with pristine sinomenine and carborane precursors, the calculations of molecular docking with matrix metalloproteinases (MMPs) and methylcarboranyl-n-butyl sinomenine showed improved interactions. Accordingly, methylcarboranyl-n-butyl sinomenine shows a high potential in the treatment of rheumatoid arthritis (RA) in the presence of slow neutrons. The reaction of potassium salt of sinomenie, which is generated from the deprotonation of sinomenine (1) using potassium carbonate in a solvent of N,N-dimethyl formamide, with 4-methylcarboranyl-n-butyl iodide, (2) forms methylcarboranyl-n-butyl sinomenine (3) in 54.3% yield as a new product. This new compound was characterized by 1H, 13C, and 11B NMR spectroscopy, FT-IR spectroscopy, and elemental analyses to confirm its molecular composition. In addition to molecular docking interactions with MMPs, the in vitro killing effects of 3, along with its toxicity measurements, exhibited its potential to be the new drug delivery agent for boron neutron capture synovectomy (BNCS) and boron neutron capture therapy (BNCT) for the treatment of rheumatoid arthritis (RA) and cancers in the presence of slow neutrons, respectively.

Synthesis, reactivity,in vitroboron neutron capture therapy assay, and molecular docking of fluorocyclocarboxyboranylamine

AbstractThe one‐pot reaction of Me3NBH2CN with Et3O+BF4−followed by addition of BF3·Et2O and water produces a trimethylamine derivative of fluorocyclocarboxyboranylamine, Me3NBH2C(O2BF2NH2) (1) in 36.0% yield. Compound1undergoes exchange reaction between the exo‐Me3N moiety and piperidine or pyridine to produce the corresponding piperidine‐substituted fluorocyclocarboxyboranylamine (2) or pyridine‐substituted fluorocyclocarboxyboranylamine (3) in 51.2% or 42.4% yields, respectively. The new compounds were characterized by1H,13C,11B, and19F nuclear magnetic resonance spectroscopy; Fourier‐transform infrared spectroscopy; and elemental analyses and the crystal structure of1was determined to confirm its molecular geometry. Thein vitrokilling effects of1, along with its toxicity measurements and molecular docking interactions with matrix metalloproteinases showed a potential promise of such species as both boron neutron capture therapy and boron neutron capture synovectomy agents in the treatment of tumors and rheumatoid arthritis, respectively, in the presence of slow neutrons.

Boron neutron capture synovectomy (BNCS) as a potential therapy for rheumatoid arthritis: radiobiological studies at RA-1 Nuclear Reactor in a model of antigen-induced arthritis in rabbits.

Rheumatoid arthritis is a chronic autoimmune pathology characterized by the proliferation and inflammation of the synovium. Boron neutron capture synovectomy (BNCS), a binary treatment modality that combines the preferential incorporation of boron carriers to target tissue and neutron irradiation, was proposed to treat the pathological synovium in arthritis. In a previous biodistribution study, we showed the incorporation of therapeutically useful boron concentrations to the pathological synovium in a model of antigen-induced arthritis (AIA) in rabbits, employing two boron compounds approved for their use in humans, i.e., decahydrodecaborate (GB-10) and boronophenylalanine (BPA). The aim of the present study was to perform low-dose BNCS studies at the RA-1 Nuclear Reactor in the same model. Neutron irradiation was performed post intra-articular administration of BPA or GB-10 to deliver 2.4 or 3.9Gy, respectively, to synovium (BNCS-AIA). AIA and healthy animals (no AIA) were used as controls. The animals were followed clinically for 2months. At that time, biochemical, magnetic resonance imaging (MRI) and histological studies were performed. BNCS-AIA animals did not show any toxic effects, swelling or pain on palpation. In BNCS-AIA, the post-treatment levels of TNF-α decreased in four of six rabbits and IFN-γ levels decreased in five of six rabbits. In all cases, MRI images of the knee joint in BNCS-AIA resembled those of no AIA, with no necrosis or periarticular effusion. Synovial membranes of BNCS-AIA were histologically similar to no AIA. BPA-BNCS and GB-10-BNCS, even at low doses, would be therapeutically useful for the local treatment of rheumatoid arthritis.

Boron neutron capture synovectomy (BNCS) as a potential therapy for rheumatoid arthritis: boron biodistribution study in a model of antigen-induced arthritis in rabbits.

Boron neutron capture synovectomy (BNCS) is explored for the treatment of rheumatoid arthritis (RA). The aim of the present study was to perform boron biodistribution studies in a model of antigen-induced arthritis (AIA) in female New Zealand rabbits, with the boron carriers boronophenylalanine (BPA) and sodium decahydrodecaborate (GB-10) to assess the potential feasibility of BNCS for RA. Rabbits in chronic phase of AIA were used for biodistribution studies employing the following protocols: intra-articular (ia) (a) BPA-f 0.14 M (0.7 mg (10)B), (b) GB-10 (5 mg (10)B), (c) GB-10 (50 mg (10)B) and intravenous (iv), (d) BPA-f 0.14 M (15.5 mg (10)B/kg), (e) GB-10 (50 mg (10)B/kg), and (f) BPA-f (15.5 mg (10)B/kg) + GB-10 (50 mg (10)B/kg). At different post-administration times (13-85 min for ia and 3 h for iv), samples of blood, pathological synovium (target tissue), cartilage, tendon, muscle, and skin were taken for boron measurement by inductively coupled plasma mass spectrometry. The intra-articular administration protocols at <40 min post-administration both for BPA-f and GB-10, and intravenous administration protocols for GB-10 and [GB-10 + BPA-f] exhibited therapeutically useful boron concentrations (>20 ppm) in the pathological synovium. Dosimetric estimations suggest that BNCS would be able to achieve a therapeutically useful dose in pathological synovium without exceeding the radiotolerance of normal tissues in the treatment volume, employing boron carriers approved for use in humans. Radiobiological in vivo studies will be necessary to determine the actual therapeutic efficacy of BNCS to treat RA in an experimental model.

Selectively induced death of macrophages in the synovial lining of murine knee joints using 10B-liposomes and boron neutron capture synovectomy

Selectively induced death of macrophages in the synovial lining of murine knee joints using 10B-liposomes and boron neutron capture synovectomy

Dose calculation from a D–D-reaction-based BSA for boron neutron capture synovectomy

Monte Carlo simulations were carried out to calculate dose in a knee phantom from a D-D-reaction-based Beam Shaping Assembly (BSA) for Boron Neutron Capture Synovectomy (BNCS). The BSA consists of a D(d,n)-reaction-based neutron source enclosed inside a polyethylene moderator and graphite reflector. The polyethylene moderator and graphite reflector sizes were optimized to deliver the highest ratio of thermal to fast neutron yield at the knee phantom. Then neutron dose was calculated at various depths in a knee phantom loaded with boron and therapeutic ratios of synovium dose/skin dose and synovium dose/bone dose were determined. Normalized to same boron loading in synovium, the values of the therapeutic ratios obtained in the present study are 12-30 times higher than the published values.

Selectively induced death of macrophages in the synovial lining of murine knee joints using 10B-liposomes and boron neutron capture synovectomy

Objective: To investigate whether macrophages in the synovial lining can be selectively eliminated by local administration of an improved boron-10 (10B) containing liposome formulation combined with neutron irradiation (boron neutron capture synovectomy [BNCS]).Methods: Disodium dodecahydrododecaborate (Na210B12H12) was encapsulated into unilamellar liposomes (10B-liposomes). 10B-liposomes were injected into the mouse knee joint. Amounts of 10B in synovial tissue were measured over time using inductively coupled plasma-optical emission spectrometry (ICP-OES). Arthritis was induced in knee joints of mice. Joint inflammation and cartilage destruction was measured using histology.Results: When a 10 μl 10B-liposome solution (containing 40 μg 10B) was injected into the murine knee joint, high concentrations of 10B were measured in macrophages in the synovial lining (At 24 h 306±226 μg. g−1 macrophages). Completing the BNCS by neutron irradiation of the legs 24 h after 10B-liposome injection showed a clear selective depletion of macrophages in synovial lining of the knee joints. An estimated total physical dose of 13±9 Gy was given to the macrophages. When arthritis was induced in the macrophage-depleted joints, swelling of the knee was significantly lower as compared to the controls (53% and 79% lower at days 1 and 3, respectively). Histology confirmed the influx of inflammatory cells was strongly decreased and severe cartilage destruction was almost completely prevented.Conclusion: BNCS using an improved 10B-containing liposome formulation can cause selective depletion of macrophages in the synovial lining of murine knee joints. As a result of this proof-of principle, future applications are recommended.

In vivo prompt gamma neutron activation analysis for the screening of boron-10 distribution in a rabbit knee: a simulation study

Boron neutron capture synovectomy (BNCS) is under development as a potential treatment modality for rheumatoid arthritis (RA). RA is characterized by the inflammation of the synovium (the membrane lining articular joints), which leads to pain and a restricted range of motion. BNCS is a two-part procedure involving the injection of a boronated compound directly into the diseased joint followed by irradiation with a low-energy neutron beam. The neutron capture reactions taking place in the synovium deliver a local, high-linear energy transfer (LET) dose aimed at destroying the inflamed synovial membrane. For successful treatment via BNCS, a boron-labeled compound exhibiting both high synovial uptake and long retention time is necessary. Currently, the in vivo uptake behavior of potentially useful boronated compounds is evaluated in the knee joints of rabbits in which arthritis has been induced. This strategy involves the sacrifice and dissection of a large number of animals. An in vivo 10B screening approach is therefore under investigation with the goal of significantly reducing the number of animals needed for compound evaluation via dissection studies. The ‘in vivo prompt gamma neutron activation analysis’ (IVPGNAA) approach uses a narrow neutron beam to irradiate the knee from several angular positions following the intra-articular injection of a boronated compound whose uptake characteristics are unknown. A high-purity germanium detector collects the 478 keV gamma photons produced by the 10B capture reactions. The 10B distribution in the knee is then reconstructed by solving a system of simultaneous equations using a weighted least squares algorithm. To study the practical feasibility of IVPGNAA, simulation data were generated with the Monte Carlo N-particle transport code. The boron-containing region of a rabbit knee was partitioned into 8 compartments, and the 10B prompt gamma signals were tallied from 16 angular positions. Results demonstrate that for this level of spatial resolution, an estimate of 10B distribution inside the joint can be obtained to within 10% uncertainty, under ideal conditions. Variations of the anatomic dimensions among individual rabbit knees and potential knee positioning errors will result in an uncertainty of over 20%. IVPGNAA thus provides sufficient resolution and quantification regarding the in vivo uptake characteristics of boronated pharmaceuticals to serve as a useful means of screening new compounds of potential use in BNCS.

Dose evaluation of boron neutron capture synovectomy using the THOR epithermal neutron beam: a feasibility study

Rheumatoid arthritis is one of the most common epidemic diseases in the world. For some patients, the treatment with steroids or nonsteroidal anti-inflammatory drugs is not effective, thus necessitating physical removal of the inflamed synovium. Alternative approaches other than surgery will provide appropriate disease control and improve the patient's quality of life. In this research, we evaluated the feasibility of conducting boron neutron capture synovectomy (BNCS) with the Tsing Hua open-pool reactor (THOR) as a neutron source. Monte Carlo simulations were performed with arthritic joint models and uncertainties were within 5%. The collimator, reflector and boron concentration were optimized to reduce the treatment time and normal tissue doses. For the knee joint, polyethylene with 40%-enriched Li2CO3 was used as the collimator material, and a rear reflector of 15 cm thick graphite and side reflector of 10 cm thick graphite were chosen. The optimized treatment time was 5.4 min for the parallel-opposed irradiation. For the finger joint, polymethyl methacrylate was used as the reflector material. The treatment time can be reduced to 3.1 min, while skin and bone doses can be effectively reduced by approximately 9% compared with treatment using the graphite reflector. We conclude that using THOR as a treatment modality for BNCS could be a feasible alternative in clinical practice.

SU‐FF‐T‐289: Initial Study On the Dose Evaluation of Boron Neutron Capture Synovectomy Using THOR Epithermal Neutron Beam

Purpose: To evaluate the feasibility of Boron Neutron Capture Synovectomy by Tsing Hua Opening‐pool Reactor (THOR) in Taiwan and to determine the optimal treatment parameters with epithermal neutron beam. Method and Materials: MCNP5 was used to model the THOR epithermal neutron beam interactions with knee and finger phantom. The phantom was established according to the structure of human joints with different boron concentration. The treatment parameters were used to model the optimum treatment assembly, such as different thickness of reflectors and beam orientations. The Figure of merits (FOMs) such as total treatment time, total maximum skin dose and synovium to bone treatment ratio were used to evaluate the effect of the treatment parameters. Results: Monte Carlo calculations predict a total therapy time of BNCS between 5 and 15 min for the human knee by optimum THOR beam assembly. The treatment parameters of BNCS vary with joint sizes. The optimum treatment condition for different joint size can be achieved by using the opposed parallel beam, placing the inflamed joint near the source, and adding 10cm side and rear graphite reflectors. To compare with BNCS using the neutron beam produced by accelerator, the THOR epithermal beam will reduce the total skin dose from 205 RBEcGy to 130.24 RBEcGy and increase the TRbone from 72 to 74.28. Conclusion: This study predicts the optimum THOR beam assembly for BNCS. The result shows the quality and overall clinical efficacy of THOR epithermal neutron beam for BNCS is more suitable than the beam produced by accelerator. It provides the potential application of BNCS by epithermal neutron beam.

Dose response of the AIA rabbit stifle joint to boron neutron capture synovectomy

This study assessed the treatment with boron neutron capture synovectomy of synovitis in the antigen-induced arthritis (AIA) model. A boron compound, potassium dodecahydrododeca-borate (K 2B 12H 12), was injected into stifle joints of 24 AIA and 12 normal rabbits and activated by neutron bombardment of the joint to achieve doses from 800 to 81,000 RBE-cGy. Synovial ablation in the AIA joint was accomplished at doses of 6,000 to 7,000 RBE-cGy with no adverse effects to skin or extracapsular tissues.

Therapeutic Applications of Monte Carlo Calculations in Nuclear Medicine

The Monte Carlo method: theory and computational issues Monte Carlo techniques in nuclear medicine dosimetry Medical imaging techniques for radiation dosimetry Computational methods in internal radiation dosimetry Mathematical models of the human anatomy Monte Carlo codes for use in therapeutic nuclear medicine Dose point kernels for radionuclide dosimetry Radiobiology aspects and radionuclide selection criteria in cancer therapy Microdosimetry of targeted radionuclides The MABDOS program for internal radionuclide dosimetry The 3D-ID three-dimensional internal dosimetry software package Validation and verification of absorbed dose calculations in radionuclide therapy Monte Carlo methods and mathematical models for the dosimetry of skeleton and bone marrow Monte Carlo modeling of dose distributions in intravascular radiation therapy The Monte Carlo method as a design tool in Boron Neutron Capture Synovectomy Summary

Solid state microdosimetry in hadron therapy.

A report of recent developments in silicon microdosimetry is presented. SOI based microdosemeters have shown promise as a viable alternative to traditional tissue-equivalent proportional counters. The application of these silicon microdosemeters to such radiation therapy modalities as boron neutron capture therapy (BNCT), boron neutron capture synovectomy (BNCS), proton therapy (PT), and fast neutron therapy (FNT) has been performed. Several shortcomings of the current silicon microdosemeter were identified and will be taken into account in the design of a second-generation device.

Optimization of Beam-Shaping Assemblies for BNCS Using the High-Energy Neutron Sources D-D and D-T

Boron neutron capture synovectomy is a novel approach for the treatment of rheumatoid arthritis. The goal of the treatment is the ablation of diseased synovial membranes in articulating joints. The treatment of knee joints is the focus of this work. A method was developed, as discussed previously, to predict the dose distribution in a knee joint from any neutron and photon beam spectra incident on the knee. This method is validated and used to design moderators for the deuterium-deuterium (D-D) and deuterium-tritium (D-T) neutron sources. Treatment times >2 h were obtained with the D-D reaction. They could potentially be reduced if the 10B concentration in the synovium was increased. For D-T neutrons, high therapeutic ratios and treatment times <5 min were obtained for neutron yields of 1014 s-1. This treatment time makes the D-T reaction attractive for boron neutron capture synovectomy.

The synthesis of corticosteroid–carborane esters for the treatment of rheumatoid arthritis via boron neutron capture synovectomy

Two corticosteroid–carborane esters were synthesized through the use of a BOP-Cl promoted esterification. The steroid–carborane conjugates are designed to selectively deliver boron to arthritic tissue for boron neutron capture synovectomy, a new therapeutic approach for rheumatoid arthritis.

Development and construction of a neutron beam line for accelerator-based boron neutron capture synovectomy

A potential application of the 10B(n, alpha)7Li nuclear reaction for the treatment of rheumatoid arthritis, termed Boron Neutron Capture Synovectomy (BNCS), is under investigation. In an arthritic joint, the synovial lining becomes inflamed and is a source of great pain and discomfort for the afflicted patient. The goal of BNCS is to ablate the synovium, thereby eliminating the symptoms of the arthritis. A BNCS treatment would consist of an intra-articular injection of boron followed by neutron irradiation of the joint. Monte Carlo radiation transport calculations have been used to develop an accelerator-based epithermal neutron beam line for BNCS treatments. The model includes a moderator/reflector assembly, neutron producing target, target cooling system, and arthritic joint phantom. Single and parallel opposed beam irradiations have been modeled for the human knee, human finger, and rabbit knee joints. Additional reflectors, placed to the side and back of the joint, have been added to the model and have been shown to improve treatment times and skin doses by about a factor of 2. Several neutron-producing charged particle reactions have been examined for BNCS, including the 9Be(p,n) reaction at proton energies of 4 and 3.7 MeV, the 9Be(d,n) reaction at deuteron energies of 1.5 and 2.6 MeV, and the 7Li(p,n) reaction at a proton energy of 2.5 MeV. For an accelerator beam current of 1 mA and synovial boron uptake of 1000 ppm, the time to deliver a therapy dose of 10,000 RBEcGy ranges from 3 to 48 min, depending on the treated joint and the neutron producing charged particle reaction. The whole-body effective dose that a human would incur during a knee treatment has been estimated to be 3.6 rem or 0.75 rem, for 1000 ppm or 19,000 ppm synovial boron uptake, respectively, although the shielding configuration has not yet been optimized. The Monte Carlo design process culminated in the construction, installation, and testing of a dedicated BNCS beam line on the high-current tandem electrostatic accelerator at the Laboratory for Accelerator Beam Applications at the Massachusetts Institute of Technology.

Boron neutron capture synovectomy: Treatment of rheumatoid arthritis based on the nuclear reaction

A novel application of the nuclear reaction for the treatment of rheumatoid arthritis is under investigation. Rheumatoid arthritis is characterized by a painful inflammation of the membrane (synovium) lining articular joints. Since the tissue targeted for treatment is the diseased synovial membrane and the goal is synovial ablation (“synovectomy”), the proposed treatment is called Boron Neutron Capture Synovectomy. Development of this therapeutic modality has been carried out in a number of areas, including the ex vivo and in vivo evaluation of in arthritic synovium, and the design and construction of a dedicated neutron beam assembly for joint irradiation. Ex vivo evaluation of boron uptake in human arthritic synovium using has demonstrated that concentrations of 550–2400 ppm are repeatedly obtained. Preliminary in vivo experiments in an arthritic rabbit model have shown that synovial boron concentrations of approximately 265–950 ppm are obtained at 15 min post intra‐articular injection. With these uptake levels experimental evaluation of the efficacy of BNCS in the treatment of rheumatoid arthritis in an animal model can be carried out. Optimal neutron beams suitable for joint irradiation are shown to be lower in energy than those used for BNCT. An assembly comprising a graphite reflector surrounding a moderator has been designed, constructed, and installed on the 4.1 MeV tandem electrostatic accelerator at MIT's Laboratory for Accelerator Beam Applications. Monte Carlo calculations predict a total therapy time of between 8.4 and 31 min for the human knee, depending on the charged particle reaction used; a particle beam current of 1 mA is assumed. Therapy times to treat a human finger joint range from 4 to 14 min for a 1 mA accelerator current. These treatment times are based on average in vivo uptake levels (observed experimentally in the rabbit knee) of 950 ppm and a 10 000 RBE‐cGy treatment dose. It is concluded that Boron Neutron Capture Synovectomy, consisting of intra‐articular injection of a ‐labeled compound followed by neutron irradiation of the joint, has considerable potential as a means of treating rheumatoid arthritis.

Characterisation of neutron and gamma-ray emission from thick target Be(p,n) reaction for boron neutron capture therapy

Low energy accelerator-based neutron sources have promising potential for use in a clinical treatment of cancer with boron neutron capture therapy (BNCT) and boron neutron capture synovectomy (BNCS). Such sources often utilise a thick target Be(p,n) reaction using incident proton energies from several hundred keV to 1–2 MeV above the reaction threshold of 2.06 MeV. The resulting neutron and gamma-ray beams require considerable moderation and filtration in order to obtain thermal and epithermal neutron fluxes for therapy. The detailed knowledge of neutron and gamma-ray spectra, yield and angular distribution are necessary in order to design effective moderators and filters to be used for the treatment. Thick and thin beryllium target neutron and gamma-ray spectra have been investigated in detail using the time-of-flight (TOF) technique, for incident proton energies from above threshold to 4 MeV. The results show characteristics of neutron and gamma-ray production of importance for the application of this neutron source for BNCT and BNCS.