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DOE OSTI2017

Intracellular delivery and passive tumor targeting of a self-assembled nanogel containing carborane clusters for boron neutron capture therapy

Boron neutron capture therapy, based on the release of thermal neutron irradiation from boron, is a targeted radiation therapy for cancer. Targeted and sufficient accumulation of boron in tumor cells to achieve cytotoxic efficacy and reduce off-target effects remains a challenge. Carborane has been investigated for use as a delivery agent in boron neutron capture therapy because of its high boron content and chemical stability; however, it is cytotoxic, making safe delivery difficult. The aim of this study was to investigate the potential of carborane-bearing pullulan nanogels to safely and effectively deliver boron to tumor cells in vitro and in vivo and, consequently, assess their potential as a boron neutron capture therapeutic. Murine fibrosarcoma cells (CMS5a) were used for in vitro investigations of nanogel cytotoxicity, cell uptake. A mouse fibrosarcoma xenograft model was used to investigate the bio-distribution of nanogels after intravenous administration. The nanogels produced no apparent cytotoxicity and underwent cell uptake in CMS5a cells after a 24 h incubation at up to 2000 μg/mL and 400 μg/mL, respectively. The internalized nanogels were localized around the nuclear membrane. The nanogels were administered intravenously to mice bearing fibrosarcoma xenografts. Nanogel tumor localization likely occurred through the enhanced permeation and retention effect. The nanogels successfully reduced the cytotoxicity of carborane, were internalized into tumor cells, acted as a dual-delivery therapeutic and accumulated in tumors in vivo. Consequently, they demonstrate significant potential as a boron neutron capture therapeutic. - Highlights: • A carborane-bearing pullulan nanogel is developed as a boron delivery agent. • The nanogels are cell-friendly and show effective cell uptake for drug delivery. • The nanogels show passive tumor targeting by enhanced permeation and retention.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Neutron-beam-shaping assembly for boron neutron-capture therapy

A neutron-beam-shaping assembly consisting of a moderator, a reflector, and an absorber is used to form a therapeutic neutron beam for the boron neutron-capture therapy of malignant tumors at accelerator neutron sources. A new structure of the moderator and reflector is proposed in the present article, and the results of a numerical simulation of the neutron spectrum and of the absorbed dose in a modified Snyder head phantom are presented. The application of a composite moderator and of a composite reflector and the implementation of neutron production at the proton energy of 2.3MeV are shown to permit obtaining a high-quality therapeutic neutron beam.

43 PARTICLE ACCELERATORS↗
DOE OSTI2016

Boron Neutron Capture Therapy in the Treatment of Recurrent Laryngeal Cancer

Purpose: To investigate the safety and efficacy of boron neutron capture therapy (BNCT) as a larynx-preserving treatment option for patients with recurrent laryngeal cancer. Methods and Materials: Six patients with locally recurrent squamous cell laryngeal carcinoma and 3 patients with persistent laryngeal cancer after prior treatment were treated with BNCT at the FiR1 facility (Espoo, Finland) in 2006 to 2012. The patients had received prior radiation therapy with or without concomitant chemotherapy to a cumulative median dose of 66 Gy. The median tumor diameter was 2.9 cm (range, 1.4-10.9 cm) before BNCT. Boron neutron capture therapy was offered on a compassionate basis to patients who either refused laryngectomy (n=7) or had an inoperable tumor (n=2). Boronophenylalanine-fructose (400 mg/kg) was used as the boron carrier and was infused over 2 hours intravenously before neutron irradiation. Results: Six patients received BNCT once and 3 twice. The estimated average gross tumor volume dose ranged from 22 to 38 Gy (W) (mean; 29 Gy [W]). Six of the 8 evaluable patients responded to BNCT; 2 achieved complete and 4 partial response. One patient died early and was not evaluable for response. Most common side effects were stomatitis, fatigue, and oral pain. No life-threatening or grade 4 toxicity was observed. The median time to progression within the target volume was 6.6 months, and the median overall survival time 13.3 months after BNCT. One patient with complete response is alive and disease-free with a functioning larynx 60 months after BNCT. Conclusions: Boron neutron capture therapy given after prior external beam radiation therapy is well tolerated. Most patients responded to BNCT, but long-term survival with larynx preservation was infrequent owing to cancer progression. Selected patients with recurrent laryngeal cancer may benefit from BNCT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Validation and Comparison of the Therapeutic Efficacy of Boron Neutron Capture Therapy Mediated By Boron-Rich Liposomes in Multiple Murine Tumor Models

Boron neutron capture therapy (BNCT) was performed at the University of Missouri Research Reactor in mice bearing CT26 colon carcinoma flank tumors and the results were compared with previously performed studies with mice bearing EMT6 breast cancer flank tumors. We implanted mice with CT26 tumors subcutaneously in the caudal flank and were given two separate tail vein injections of unilamellar liposomes composed of cholesterol, 1,2-distearoyl-sn-glycer-3-phosphocholine, and K[nido-7-CH 3 (CH 2 ) 15 –7,8-C 2 B 9 H 11 ] in the lipid bilayer and encapsulated Na 3 [1-(2`-B 10 H 9 )-2-NH 3 B 10 H 8 ] within the liposomal core. Mice were irradiated 30 hours after the second injection in a thermal neutron beam for various lengths of time. The tumor size was monitored daily for 72 days. In spite of relatively lower tumor boron concentrations, as compared to EMT6 tumors, a 45 minute neutron irradiation BNCT resulted in complete resolution of the tumors in 50% of treated mice, 50% of which never recurred. Median time to tumor volume tripling was 38 days in BNCT treated mice, 17 days in neutron-irradiated mice given no boron compounds, and 4 days in untreated controls. Tumor response in mice with CT26 colon carcinoma was markedly more pronounced than in previous reports of mice with EMT6 tumors, a difference which increased with dose. The slope of the dose response curve of CT26 colon carcinoma tumors is 1.05 times tumor growth delay per Gy compared to 0.09 times tumor growth delay per Gy for EMT6 tumors, indicating that inherent radiosensitivity of tumors plays a role in boron neutron capture therapy and should be considered in the development of clinical applications of BNCT in animals and man.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial

Purpose: To investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy. Methods and Materials: In this prospective phase 1/2 trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA–positron emission tomography was conducted to determine the tumor/normal tissue ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively. Results: Seventeen patients with a previous cumulative radiation dose of 63-165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median tumor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants exhibited a complete response and 6 exhibited a partial response. Regarding acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40 Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locoregional control was 28%. Conclusions: Our results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H&N cancer. Modifications to our protocol may yield more satisfactory results in the future.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Development of an Accelerator-Based Epithermal Neutron Source for Boron Neutron Capture Therapy

The paper presents a review of the current state of development of accelerator-based epithermal neutron sources for boron neutron capture therapy (BNCT), a promising method for the treatment of malignant tumors. Special attention is paid to an epithermal neutron source based on a new type of accelerator of charged particles: a tandem accelerator with vacuum insulation and a lithium neutron-producing target.

43 PARTICLE ACCELERATORS↗
DOE OSTI2015

Development of a dual phantom technique for measuring the fast neutron component of dose in boron neutron capture therapy

Purpose: Research and development of various accelerator-based irradiation systems for boron neutron capture therapy (BNCT) is underway throughout the world. Many of these systems are nearing or have started clinical trials. Before the start of treatment with BNCT, the relative biological effectiveness (RBE) for the fast neutrons (over 10 keV) incident to the irradiation field must be estimated. Measurements of RBE are typically performed by biological experiments with a phantom. Although the dose deposition due to secondary gamma rays is dominant, the relative contributions of thermal neutrons (below 0.5 eV) and fast neutrons are virtually equivalent under typical irradiation conditions in a water and/or acrylic phantom. Uniform contributions to the dose deposited from thermal and fast neutrons are based in part on relatively inaccurate dose information for fast neutrons. This study sought to improve the accuracy in the dose estimation for fast neutrons by using two phantoms made of different materials in which the dose components can be separated according to differences in the interaction cross sections. The development of a “dual phantom technique” for measuring the fast neutron component of dose is reported. Methods: One phantom was filled with pure water. The other phantom was filled with a water solution of lithium hydroxide (LiOH) capitalizing on the absorbing characteristics of lithium-6 (Li-6) for thermal neutrons. Monte Carlo simulations were used to determine the ideal mixing ratio of Li-6 in LiOH solution. Changes in the depth dose distributions for each respective dose component along the central beam axis were used to assess the LiOH concentration at the 0, 0.001, 0.01, 0.1, 1, and 10 wt. % levels. Simulations were also performed with the phantom filled with 10 wt. % {sup 6}LiOH solution for 95%-enriched Li-6. A phantom was constructed containing 10 wt. % {sup 6}LiOH solution based on the simulation results. Experimental characterization of the depth dose distributions of the neutron and gamma-ray components along the central axis was performed at Heavy Water Neutron Irradiation Facility installed at Kyoto University Reactor using activation foils and thermoluminescent dosimeters, respectively. Results: Simulation results demonstrated that the absorbing effect for thermal neutrons occurred when the LiOH concentration was over 1%. The most effective Li-6 concentration was determined to be enriched {sup 6}LiOH with a solubility approaching its upper limit. Experiments confirmed that the thermal neutron flux and secondary gamma-ray dose rate decreased substantially; however, the fast neutron flux and primary gamma-ray dose rate were hardly affected in the 10%-{sup 6}LiOH phantom. It was confirmed that the dose contribution of fast neutrons is improved from approximately 10% in the pure water phantom to approximately 50% in the 10%-{sup 6}LiOH phantom. Conclusions: The dual phantom technique using the combination of a pure water phantom and a 10%-{sup 6}LiOH phantom developed in this work provides an effective method for dose estimation of the fast neutron component in BNCT. Improvement in the accuracy achieved with the proposed technique results in improved RBE estimation for biological experiments and clinical practice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-T-183: Design of a Beam Shaping Assembly of a Compact DD-Based Boron Neutron Capture Therapy System

Purpose: To design a beam shaping assembly (BSA) to shape the 2.45-MeV neutrons produced by a deuterium-deuterium (DD) neutron generator and to optimize the beam output for boron neutron capture therapy of brain tumors Methods: MCNP is used for this simulation study. The simulation model consists of a neutron surface source that resembles an actual DD source and is surrounded by a BSA. The neutron source emits 2.45-MeV neutrons isotropically. The BSA is composed of a moderator, reflector, collimator and filter. Various types of materials and geometries are tested for each component to optimize the neutron output. Neutron characteristics are measured with an 2×2×2-cm{sup 3} air-equivalent cylinder at the beam exit. The ideal BSA is determined by evaluating the in-air parameters, which include epithermal neutron per source neutron, fast neutron dose per epithermal neutron, and photon dose per epithermal neutron. The parameter values are compared to those recommended by the IAEA. Results: The ideal materials for reflector and thermal neutron filter were lead and cadmium, respectively. The thickness for reflector was 43 cm and for filter was 0.5 mm. At present, the best-performing moderator has 25 cm of AlF{sub 3} and 5 cm of MgF{sub 2}. This layout creates a neutron spectrum that has a peak at approximately 10 keV and produces 1.35E-4 epithermal neutrons per source neutron per cm{sup 2}. Additional neutron characteristics, fast neutrons per epithermal neutron and photon per epithermal neutron, are still under investigation. Conclusion: Working is ongoing to optimize the final layout of the BSA. The neutron spectrum at the beam exit window of the final configuration will have the maximum number of epithermal neutrons and limited photon and fast neutron contaminations within the recommended values by IAEA. Future studies will also include phantom experiments to validate the simulation results.

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2016

TU-FG-BRB-07: GPU-Based Prompt Gamma Ray Imaging From Boron Neutron Capture Therapy

Purpose: The purpose of this research is to perform the fast reconstruction of a prompt gamma ray image using a graphics processing unit (GPU) computation from boron neutron capture therapy (BNCT) simulations. Methods: To evaluate the accuracy of the reconstructed image, a phantom including four boron uptake regions (BURs) was used in the simulation. After the Monte Carlo simulation of the BNCT, the modified ordered subset expectation maximization reconstruction algorithm using the GPU computation was used to reconstruct the images with fewer projections. The computation times for image reconstruction were compared between the GPU and the central processing unit (CPU). Also, the accuracy of the reconstructed image was evaluated by a receiver operating characteristic (ROC) curve analysis. Results: The image reconstruction time using the GPU was 196 times faster than the conventional reconstruction time using the CPU. For the four BURs, the area under curve values from the ROC curve were 0.6726 (A-region), 0.6890 (B-region), 0.7384 (C-region), and 0.8009 (D-region). Conclusion: The tomographic image using the prompt gamma ray event from the BNCT simulation was acquired using the GPU computation in order to perform a fast reconstruction during treatment. The authors verified the feasibility of the prompt gamma ray reconstruction using the GPU computation for BNCT simulations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Experimental Studies of Boronophenylalanine ({sup 10}BPA) Biodistribution for the Individual Application of Boron Neutron Capture Therapy (BNCT) for Malignant Melanoma Treatment

Purpose: Patients with the same histopathologic diagnosis of cutaneous melanoma treated with identical protocols of boron neutron capture therapy (BNCT) have shown different clinical outcomes. The objective of the present studies was to evaluate the biodistribution of boronophenilalanina ({sup 10}BPA) for the potential application of BNCT for the treatment of melanoma on an individual basis. Methods and Materials: The boronophenilalanine (BPA) uptake was evaluated in 3 human melanoma cell lines: MEL-J, A375, and M8. NIH nude mice were implanted with 4 10{sup 6} MEL-J cells, and biodistribution studies of BPA (350 mg/kg intraperitoneally) were performed. Static infrared imaging using a specially modified infrared camera adapted to measure the body infrared radiance of small animals was used. Proliferation marker, Ki-67, and endothelial marker, CD31, were analyzed in tumor samples. Results: The in vitro studies demonstrated different patterns of BPA uptake for each analyzed cell line (P<.001 for MEL-J and A375 vs M8 cells). The in vivo studies showed a maximum average boron concentration of 25.9 ± 2.6 μg/g in tumor, with individual values ranging between 11.7 and 52.0 μg/g of {sup 10}B 2 hours after the injection of BPA. Tumor temperature always decreased as the tumors increased in size, with values ranging between 37°C and 23°C. A significant correlation between tumor temperature and tumor-to-blood boron concentration ratio was found (R{sup 2} = 0.7, rational function fit). The immunohistochemical studies revealed, in tumors with extensive areas of viability, a high number of positive cells for Ki-67, blood vessels of large diameter evidenced by the marker CD31, and a direct logistic correlation between proliferative status and boron concentration difference between tumor and blood (R{sup 2} = 0.81, logistic function fit). Conclusion: We propose that these methods could be suitable for designing new screening protocols applied before melanoma BNCT treatment for each individual patient and lesion.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Simulation Environment For Radiotherapy Applications

SERA is a simulation environment for planning three-dimensional neutron capture therapy. SERA can allows creating models of the geometry of the tumor and surrounding tissue from CT or MRI data, and then planning and simulating the treatment of the tumor with Boron Neutron Capture Therapy. Boron Neutron Capture Therapy uses the combination of a boron containing drug and a neutron source to treat a tumor.

Cogliati, JoshuaJ. [Idaho National Laboratory (INL↗
DOE OSTI2015

High yield neutron generator based on a high-current gasdynamic electron cyclotron resonance ion source

In present paper, an approach for high yield compact D-D neutron generator based on a high current gasdynamic electron cyclotron resonance ion source is suggested. Results on dense pulsed deuteron beam production with current up to 500 mA and current density up to 750 mA/cm{sup 2} are demonstrated. Neutron yield from D{sub 2}O and TiD{sub 2} targets was measured in case of its bombardment by pulsed 300 mA D{sup +} beam with 45 keV energy. Neutron yield density at target surface of 10{sup 9} s{sup −1} cm{sup −2} was detected with a system of two {sup 3}He proportional counters. Estimations based on obtained experimental results show that neutron yield from a high quality TiD{sub 2} target bombarded by D{sup +} beam demonstrated in present work accelerated to 100 keV could reach 6 × 10{sup 10} s{sup −1} cm{sup −2}. It is discussed that compact neutron generator with such characteristics could be perspective for a number of applications like boron neutron capture therapy, security systems based on neutron scanning, and neutronography.

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2024

Ultrathin Boron Growth onto Nanodiamond Surfaces via Electrophilic Boron Precursors

Diamond as a templating substrate is largely unexplored, and the unique properties of diamond, including its large bandgap, thermal conductance, and lack of cytotoxicity, makes it versatile in emergent technologies in medicine and quantum sensing. Surface termination of an inert diamond substrate and its chemical reactivity are key in generating new bonds for nucleation and growth of an overlayer material. Oxidized high-pressure high temperature (HPHT) nanodiamonds (NDs) are largely terminated by alcohols that act as nucleophiles to initiate covalent bond formation when an electrophilic reactant is available. In this work, we demonstrate a templated synthesis of ultrathin boron on ND surfaces using trigonal boron compounds. Boron trichloride (BCl 3 ), boron tribromide (BBr 3 ), and borane (BH 3 ) were found to react with ND substrates at room temperature in inert conditions. BBr 3 and BCl 3 were highly reactive with the diamond surface, and sheet-like structures were produced and verified with electron microscopy. Surface-sensitive spectroscopies were used to probe the molecular and atomic structure of the ND constructs’ surface, and quantification showed the boron shell was less than 1 nm thick after 1–24 h reactions. Observation of the reaction supports a self-terminating mechanism, similar to atomic layer deposition growth, and is likely due to the quenching of alcohols on the diamond surface. X-ray absorption spectroscopy revealed that boron-termination generated midgap electronic states that were originally predicted by density functional theory (DFT) several years ago. DFT also predicted a negative electron surface, which has yet to be confirmed experimentally here. The boron-diamond nanostructures were found to aggregate in dichloromethane and were dispersed in various solvents and characterized with dynamic light scattering for future cell imaging or cancer therapy applications using boron neutron capture therapy (BNCT). The unique templating mechanism based on nucleophilic alcohols and electrophilic trigonal precursors allows for covalent bond formation and will be of interest to researchers using diamond for quantum sensing, additive manufacturing, BNCT, and potentially as an electron emitter.

36 MATERIALS SCIENCE↗
DOE OSTI2015

Accelerator based epithermal neutron source

We review the current status of the development of accelerator sources of epithermal neutrons for boron neutron capture therapy (BNCT), a promising method of malignant tumor treatment. Particular attention is given to the source of epithermal neutrons on the basis of a new type of charged particle accelerator: tandem accelerator with vacuum insulation and lithium neutron-producing target. It is also shown that the accelerator with specialized targets makes it possible to generate fast and monoenergetic neutrons, resonance and monoenergetic gamma-rays, alpha-particles, and positrons.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2016

Criticality Benchmarking of the Oregon State TRIGA Reactor Using the MCNP Burn Option

Neutronic analyses of the Oregon State TRIGA Reactor (OSTR) have historically been performed using a thoroughly validated MCNP model. This model was originally created in 1997 in support of boron neutron capture therapy (BNCT) research, when the core still utilized highly-enriched uranium (HEU) fuel. The OSTR core was converted to low-enriched uranium (LEU) in the fall of 2008. To more accurately represent the converted state of the core, the MCNP model was modified to incorporate fuel material information from the fuel manufacturer (AREVA). In previous versions of the model, the fuel elements were assumed to have a uniform isotopic composition. Chemical analysis from AREVA provided far more resolved material information, allowing for increased fidelity in the representation of the fuel. The model was also updated to ENDF/B-VII.1 cross section libraries as the previous model utilized ENDF/B-VI. The primary impetus for the update of the MCNP model was the desire to have a more accurate assessment of criticality conditions of the OSTR. The OSTR utilizes three core configurations which are defined by the contents of the B1 grid position. If fuel resides in B1, this is designated as the 'normal' core. Otherwise, there are two aluminum in-core irradiation tubes (ICITs) that can be placed in B1. There is an unlined tube, designated simply as the ICIT, and there is a cadmium-lined tube, designated as the CLICIT. Table 1 contains a summary of the results of a series of MCNP criticality calculations which used the original 'fresh fuel' isotopics from the fall of 2008 in conjunction with critical rod height data from December 2013. Calculations were performed at 15 W, which is where the daily core excess measurements are taken, and at 1 MW, which is the current full-power level at the OSTR. The k-effective values indicate that the fresh fuel material cards are highly inaccurate and over-predict the criticality by at least $1.20 in every core configuration (based on a β{sub eff} value of 0.0075), thus it was desired to perform a depletion calculation to obtain more accurate fuel information. (authors)

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗