Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation for BNCT in a Rat Melanoma Model

Recently, exploitation of cerebrospinal fluid (CSF) circulation has become increasingly recognized as a feasible strategy to solve the challenges involved in drug delivery for treating brain tumors. Boron neutron capture therapy (BNCT) also faces challenges associated with the development of an efficient delivery system for boron, especially to brain tumors. Our laboratory has been developing a system for boron delivery to brain cells using CSF, which we call the “boron CSF administration method”. In our previous study, we found that boron was efficiently delivered to the brain cells of normal rats in the form of small amounts of L-p-boronophenylalanine (BPA) using the CSF administration method. In the study described here, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. We first investigated the boron concentration of the brain cells every 60 min after BPA administration into the lateral ventricle of normal rats. Second, we measured and compared the boron concentration in the melanoma model rats after administering boron via either the CSF administration method or the intravenous (IV) administration method, with estimation of the T/N ratio. Our results revealed that boron injected by the CSF administration method was excreted quickly from normal cells, resulting in a high T/N ratio compared to that of IV administration. In addition, the CSF administration method resulted in high boron accumulation in tumor cells. In conclusion, we found that using our developed CSF administration method results in more selective delivery of boron to the brain tumor compared with the IV administration method

Feasibility study on real-time γ-ray spectrum / dose measurement system

Recently, medical applications of radiation have been widely spread. However, exposure of medical staffs is sometimes not focused on because treatment of patients is the first priority. It is thus important to decrease exposure for them as much as possible. The purpose of this study is to develop a system which can measure energy spectrum and dose of gamma-rays at the same time in real time in medical application spots. As a result, the medical staff could be guided to aware the risk of radiation and finally the exposure dose to them could be suppressed substantially. We first decided to use a CsI(Tl) scintillator as the gamma-ray detection device. A Multi-Pixel Photon Counter (MPPC) was attached to the scintillator to detect gamma-ray signals. Pulse height spectra were measured with several standard gamma-ray sources. The detection efficiency and energy resolution were deduced from the measured results and the detection efficiency was compared with the calculation result by MCNP5. After evaluating the response function, the energy spectrum was derived with the spectrum type Bayesian estimation and the sequential Bayesian estimation procedure. From the result, it was confirmed that the sequential Bayesian estimation could be applied to real time measurement of gamma-ray energy spectrum and dose

Feasibility study on real-time γ-ray spectrum / dose measurement system

Recently, medical applications of radiation have been widely spread. However, exposure of medical staffs is sometimes not focused on because treatment of patients is the first priority. It is thus important to decrease exposure for them as much as possible. The purpose of this study is to develop a system which can measure energy spectrum and dose of gamma-rays at the same time in real time in medical application spots. As a result, the medical staff could be guided to aware the risk of radiation and finally the exposure dose to them could be suppressed substantially. We first decided to use a CsI(Tl) scintillator as the gamma-ray detection device. A Multi-Pixel Photon Counter (MPPC) was attached to the scintillator to detect gamma-ray signals. Pulse height spectra were measured with several standard gamma-ray sources. The detection efficiency and energy resolution were deduced from the measured results and the detection efficiency was compared with the calculation result by MCNP5. After evaluating the response function, the energy spectrum was derived with the spectrum type Bayesian estimation and the sequential Bayesian estimation procedure. From the result, it was confirmed that the sequential Bayesian estimation could be applied to real time measurement of gamma-ray energy spectrum and dose

Thought Experiment to Examine Benchmark Performance for Fusion Nuclear Data

There are many benchmark experiments carried out so far with DT neutrons especially aiming at fusion reactor development. These integral experiments seemed vaguely to validate the nuclear data below 14 MeV. However, no precise studies exist now. The author’s group thus started to examine how well benchmark experiments with DT neutrons can play a benchmarking role for energies below 14 MeV. Recently, as a next phase, to generalize the above discussion, the energy range was expanded to the entire region. In this study, thought experiments with finer energy bins have thus been conducted to discuss how to generally estimate performance of benchmark experiments. As a result of thought experiments with a point detector, the sensitivity for a discrepancy appearing in the benchmark analysis is “equally” due not only to contribution directly conveyed to the deterctor, but also due to indirect contribution of neutrons (named (A)) making neutrons conveying the contribution, indirect controbution of neutrons (B) making the neutrons (A) and so on. From this concept, it would become clear from a sensitivity analysis in advance how well and which energy nuclear data could be benchmarked with a benchmark experiment

Development of An Epi-thermal Neutron Field for Fundamental Researches for BNCT with A DT Neutron Source

Boron Neutron Capture Therapy (BNCT) is known to be a new promising cancer therapy suppressing influence against normal cells. In Japan, Accelerator Based Neutron Sources (ABNS) are being developed for BNCT. For the spread of ABNS based BNCT, we should characterize the neutron field beforehand. For this purpose, we have been developing a low-energy neutron spectrometer based on 3He position sensitive proportional counter. In this study, a new intense epi-thermal neutron field was developed with a DT neutron source for verification of validity of the spectrometer. After the development, the neutron field characteristics were experimentally evaluated by using activation foils. As a result, we confirmed that an epi-thermal neutron field was successfully developed suppressing fast neutrons substantially. Thereafter, the neutron spectrometer was verified experimentally. In the verification, although a measured detection depth distribution agreed well with the calculated distribution by MCNP, the unfolded spectrum was significantly different from the calculated neutron spectrum due to contribution of the side neutron incidence. Therefore, we designed a new neutron collimator consisting of a polyethylene pre-collimator and boron carbide neutron absorber and confirmed numerically that it could suppress the side incident neutrons and shape the neutron flux to be like a pencil beam

Development of An Epi-thermal Neutron Field for Fundamental Researches for BNCT with A DT Neutron Source

Boron Neutron Capture Therapy (BNCT) is known to be a new promising cancer therapy suppressing influence against normal cells. In Japan, Accelerator Based Neutron Sources (ABNS) are being developed for BNCT. For the spread of ABNS based BNCT, we should characterize the neutron field beforehand. For this purpose, we have been developing a low-energy neutron spectrometer based on 3He position sensitive proportional counter. In this study, a new intense epi-thermal neutron field was developed with a DT neutron source for verification of validity of the spectrometer. After the development, the neutron field characteristics were experimentally evaluated by using activation foils. As a result, we confirmed that an epi-thermal neutron field was successfully developed suppressing fast neutrons substantially. Thereafter, the neutron spectrometer was verified experimentally. In the verification, although a measured detection depth distribution agreed well with the calculated distribution by MCNP, the unfolded spectrum was significantly different from the calculated neutron spectrum due to contribution of the side neutron incidence. Therefore, we designed a new neutron collimator consisting of a polyethylene pre-collimator and boron carbide neutron absorber and confirmed numerically that it could suppress the side incident neutrons and shape the neutron flux to be like a pencil beam

Design study of benchmark experiment for large-angle scattering cross section for non-solid target with 14 MeV neutron

Accuracy of large-angle scattering cross section in nuclear data has a large contribution on precision of neutron transport calculation in fusion reactor design. In the previous research, benchmark experiments for a solid target were carried out, however, non-solid targets, which are enclosed in a container, could not be dealt with. This is because we were not able to remove the effect due to existence of the container in the previous method. In this study, we performed design study of advanced benchmark experiment for large-angle scattering cross section especially for a non-solid target in a container. In addition, we also carried out benchmark experiments for silicon, which is important for the fusion reactor, however, is one of the elements that are difficult to obtain a solid target. In conclusion, we successfully developed an advanced benchmark experimental method for non-solid targets and verified it numerically by Monte Carlo calculation. In addition, we also found experimentally that large-angle scattering cross section of silicon is underestimated in JENDL-4, ENDF-B/VIII and JEFF-3.3

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation in BNCT of Brain-Tumor-Model Rats—Ex Vivo Imaging of BPA Using MALDI Mass Spectrometry Imaging

The blood–brain barrier (BBB) is likely to be intact during the early stages of brain metastatic melanoma development, and thereby inhibits sufficient drug delivery into the metastatic lesions. Our laboratory has been developing a system for boron drug delivery to brain cells via cerebrospinal fluid (CSF) as a viable pathway to circumvent the BBB in boron neutron capture therapy (BNCT). BNCT is a cell-selective cancer treatment based on the use of boron-containing drugs and neutron irradiation. Selective tumor targeting by boron with minimal normal tissue toxicity is required for effective BNCT. Boronophenylalanine (BPA) is widely used as a boron drug for BNCT. In our previous study, we demonstrated that application of the CSF administration method results in high BPA accumulation in the brain tumor even with a low dose of BPA. In this study, we evaluate BPA biodistribution in the brain following application of the CSF method in brain-tumor-model rats (melanoma) utilizing matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). We observed increased BPA penetration to the tumor tissue, where the color contrast on mass images indicates the border of BPA accumulation between tumor and normal cells. Our approach could be useful as drug delivery to different types of brain tumor, including brain metastases of melanoma