用于硼中子俘获治疗的超热中子束理论设计

目的 设计用于硼中子俘获治疗(BNCT)的超热中子束理论方案。方法 基于清华大学试验核反应堆,以其1号孔道为材料布放孔道,设计了由慢化材料、热中子吸收材料、γ屏蔽材料组成,但材料布放位置具有差异的5种理论方案;利用蒙特卡罗(MC)模拟方法,分别计算5种方案束出口处的中子注量率、剂量率及γ剂量率值,通过与BNCT技术指标对比,从5种方案中选择一种合适的方案。结果 得到了一个符合BNCT各项技术指标的超热中子束理论方案,其慢化材料厚度为53.5 cm、热中子吸收材料厚度为2 mm、γ屏蔽材料厚度为9 cm。结论 本研究给出的超热中子束理论方案为基于反应堆实现BNCT提供一定的理论参考。     

Drug delivery system design and development for boron neutron capture therapy on cancer treatment

We have already synthesized a boron-containing polymeric micellar drug delivery system for boron neutron capture therapy (BNCT). The synthesized diblock copolymer, boron-terminated copolymers (Bpin-PLA-PEOz), consisted of biodegradable poly(D,l-lactide) (PLA) block and water-soluble polyelectrolyte poly(2-ethyl-2-oxazoline) (PEOz) block, and a cap of pinacol boronate ester (Bpin). In this study, we have demonstrated that synthesized Bpin-PLA-PEOz micelle has great potential to be boron drug delivery system with preliminary evaluation of biocompatibility and boron content.     

Synthesis of conjugates of polyhedral boron compounds with tumor-seeking molecules for neutron capture therapy

Recent achievements in design and synthesis of boronated acids, amino acids, glycerols as well as conjugates of polyhedral boron hydrides (ortho-carborane, closo-dodecaborate and cobalt bis(dicarbollide)) with natural porphyrins, carbohydrates and nucleosides are described.     

Boron neutron capture therapy combined with fractionated photon irradiation for glioblastoma: A recursive partitioning analysis of BNCT patients

Eight patients to received Boron Neuron Capture Therapy (BNCT) were selected from 33 newly diagnosed glioblastoma patients (NCT(+) group). Serial 42 glioblastoma patients (NCT(−) group) were treated without BNCT. The median OS of the NCT(+) group and NCT (−) group were 24.4 months and 14.9 months. In the high risk patients (RPA class V), the median OS of the NCT(+) group tended to be better than that of NCT(−) group. 50% of BNCT patients were RPA class V.     

Effects of l-DOPA pre-loading on the uptake of boronophenylalanine using the F98 glioma and B16 melanoma models

The present study was undertaken to evaluate the effects of l-DOPA pre-loading on the uptake of BPA using the F98 rat glioma and the murine B16 melanoma models. In vitro pretreatments of F98 glioma and B16 melanoma cells with l-DOPA, followed by exposure to BPA increased boron uptake, as determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). Based on this, in vivo studies were initiated in F98 glioma bearing rats. Initially, the l-DOPA dosing paradigm was evaluated. Maximum tumor boron uptake was observed following i.p. administration of l-DOPA (50 mg/kg) followed 24 h later by BPA (31.8±8.9 vs. 17.2±6.3 µg/g for BPA alone). Next, the effect of l-DOPA pre-loading as a function of the route of administration of BPA was evaluated in F98 glioma bearing rats. The greatest increase in uptake was seen following i.v. administration of BPA, while in contrast no significant increase was seen following intracarotid (i.c.) administration (38.6±12.4 vs. 34.2±10.9). Cellular localization of the F98 glioma, as determined by secondary ion mass spectrometry (SIMS) boron imaging revealed equivalent tumor boron concentrations following l-DOPA pre-loading. In vivo studies in B16 melanoma bearing mice showed equivalent tumor boron values in treated and untreated mice, suggesting that the effects of l-DOPA pre-loading may depend both on the histologic type of tumor and its anatomic site.     

Translational boron neutron capture therapy (BNCT) studies for the treatment of tumors in lung

Abstract

Purpose: Boron neutron capture therapy (BNCT) combines selective accumulation of ¹⁰B carriers in tumor tissue with subsequent neutron irradiation. BNCT has been proposed for the treatment of multiple, non-resectable, diffuse tumors in lung. The aim of the present study was to evaluate the therapeutic efficacy and toxicity of BNCT in an experimental model of lung metastases of colon carcinoma in BDIX rats and perform complementary survival studies.

Materials and methods: We evaluated tumor control and toxicity in lung 2?weeks post-BNCT at 2 dose levels, including 5 experimental groups per dose level: T0 (euthanized pre-treatment), Boronophenylalanine-BNCT (BPA-BNCT), BPA?+?Sodium decahydrodecaborate-BNCT ((BPA?+?GB-10)-BNCT), Beam only (BO) and Sham (no treatment, same manipulation). Tumor response was assessed employing macroscopic and microscopic end-points. An additional experiment was performed to evaluate survival and oxygen saturation in blood.

Results and conclusions: No dose-limiting signs of short/medium-term toxicity were observed in lung. All end-points revealed statistically significant BNCT-induced tumor control vs Sham at both dose levels. The survival experiment showed a statistically significant 45% increase in post-treatment survival time in the BNCT group (48?days) versus Sham (33?days). These data consistently revealed growth suppression of lung metastases by BNCT with no manifest lung toxicity.

• Highlights

• Boron Neutron Capture Therapy suppresses growth of experimental lung metastases

• No BNCT-induced short/medium-term toxicity in lung is associated with tumor control

• Boron Neutron Capture Therapy increased post-treatment survival time by 45%

     

Liposome-based delivery of a boron-containing cholesteryl ester for high-LET particle-induced damage of prostate cancer cells: A boron neutron capture therapy study

Abstract

Purpose: The efficacy of a boron-containing cholesteryl ester compound (BCH) as a boron neutron capture therapy (BNCT) agent for the targeted irradiation of PC-3 human prostate cancer cells was examined.

Materials and methods: Liposome-based delivery of BCH was quantified with inductively coupled plasma-mass spectrometry (ICP-MS) and high-performance liquid chromatography (HPLC). Cytotoxicity of the BCH-containing liposomes was evaluated with neutral red, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), and lactate dehydrogenase assays. Colony formation assays were utilized to evaluate the decrease in cell survival due to high-linear energy transfer (LET) particles resulting from ¹⁰B thermal neutron capture.

Results: BCH delivery by means of encapsulation in a lipid bilayer resulted in a boron uptake of 35.2 ± 4.3 μg/10⁹ cells, with minimal cytotoxic effects. PC-3 cells treated with BCH and exposed to a 9.4 × 10¹¹ n/cm² thermal neutron fluence yielded a 20–25% decrease in clonogenic capacity. The decreased survival is attributed to the generation of high-LET α particles and ⁷Li nuclei that deposit energy in densely ionizing radiation tracks.

Conclusion: Liposome-based delivery of BCH is capable of introducing sufficient boron to PC-3 cells for BNCT. High-LET α particles and ⁷Li nuclei generated from ¹⁰B thermal neutron capture significantly decrease colony formation ability in the targeted PC-3 cells.     

High-power electron beam tests of a liquid-lithium target and characterization study of 7Li(p,n) near-threshold neutrons for accelerator-based boron neutron capture therapy

A compact Liquid-Lithium Target (LiLiT) was built and tested with a high-power electron gun at Soreq Nuclear Research Center (SNRC). The target is intended to demonstrate liquid-lithium target capabilities to constitute an accelerator-based intense neutron source for Boron Neutron Capture Therapy (BNCT) in hospitals. The lithium target will produce neutrons through the ⁷Li(p,n)⁷Be reaction and it will overcome the major problem of removing the thermal power >5 kW generated by high-intensity proton beams, necessary for sufficient therapeutic neutron flux.In preliminary experiments liquid lithium was flown through the target loop and generated a stable jet on the concave supporting wall. Electron beam irradiation demonstrated that the liquid-lithium target can dissipate electron power densities of more than 4 kW/cm² and volumetric power density around 2 MW/cm³ at a lithium flow of ~4 m/s, while maintaining stable temperature and vacuum conditions. These power densities correspond to a narrow (σ=~2 mm) 1.91 MeV, 3 mA proton beam. A high-intensity proton beam irradiation (1.91–2.5 MeV, 2 mA) is being commissioned at the SARAF (Soreq Applied Research Accelerator Facility) superconducting linear accelerator.In order to determine the conditions of LiLiT proton irradiation for BNCT and to tailor the neutron energy spectrum, a characterization of near threshold (~1.91 MeV) ⁷Li(p,n) neutrons is in progress based on Monte-Carlo (MCNP and Geant4) simulation and on low-intensity experiments with solid LiF targets. In-phantom dosimetry measurements are performed using special designed dosimeters based on CR-39 track detectors.     

Visualization of the protective ability of a free radical trapping compound against rat C6 and F98 gliomas with diffusion tensor fiber tractography

PURPOSE: To apply fiber tractography to assess the effect of a possible antiglioma drug, phenyl N-tert-butyl nitrone (PBN), on glioma-affected neuronal fibers. The fiber tractography method was able to differentiate between different tumor types, such as the C6 and F98 rat glioma models. MATERIALS AND METHODS: C6 or F98 cells were intracranially injected into the cortex of male Fischer 344 rats. PBN treatment was initiated before or after cell implantation. Tumor growth was monitored with diffusion tensor imaging (DTI) and fiber tractography using diffusion-weighting gradients in 30 noncolinear directions. RESULTS: Although proton density-weighted (PDw) and T2-weighted (T2w) images did not show any difference between C6 and F98 gliomas without edema, the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were able to discriminate between these two tumor models. Fiber tractography was used to visualize C6 glioma-induced ischemia of tumor-surrounding tissues, whereas F98 glioma was found to infiltrate and penetrate into the corpus callosum (CC). During glioma growth, neuronal fibers were found to disappear at the border regions between the tumor and surrounding tissues. PBN treatment was shown to inhibit glioma growth with accompanying changes in the surrounding tissue. CONCLUSION: By noninvasively monitoring the degree of neuronal fiber integrity and connectivity with the use of neuronal fiber tractography, we were able to evaluate the protective effect of PBN against invasive glioma growth in rat brains. PBN provided protection of the neuronal fibers against tumor-induced ischemia and tumor invasion.     

Feasibility evaluation of neutron capture therapy for hepatocellular carcinoma using selective enhancement of boron accumulation in tumour with intra-arterial administration of boron-entrapped water-in-oil-in-water emulsion

Introduction

Hepatocellular carcinoma (HCC) is one of the most difficult to cure with surgery, chemotherapy, or other combinational therapies. In the treatment of HCC, only 30% patients can be operated due to complication of liver cirrhosis or multiple intrahepatic tumours. Tumour cell destruction in boron neutron-capture therapy (BNCT) is due to the nuclear reaction between ¹⁰B atoms and thermal neutrons, so it is necessary to accumulate a sufficient quantity of ¹⁰B atoms in tumour cells for effective tumour cell destruction by BNCT. Water-in-oil-in-water (WOW) emulsion has been used as the carrier of anti-cancer agents on intra-arterial injections in clinical. In this study, we prepared ¹⁰BSH entrapped WOW emulsion by double emulsifying technique using iodized poppy-seed oil (IPSO), ¹⁰BSH and surfactant, for selective intra-arterial infusion to HCC, and performed simulations of the irradiation in order to calculate the dose delivered to the patients.

Materials and methods

WOW emulsion was administrated with intra-arterial injections via proper hepatic artery on VX-2 rabbit hepatic tumour models. We simulated the irradiation of epithermal neutron and calculated the dose delivered to the tissues with JAEA computational dosimetry system (JCDS) at JRR4 reactor of Japan Atomic Research Institute, using the CT scans of a HCC patient.

Results and discussions

The ¹⁰B concentrations in VX-2 tumour obtained by delivery with WOW emulsion were superior to those by conventional IPSO mix emulsion. According to the rabbit model, the boron concentrations (ppm) in tumour, normal liver tissue, and blood are 61.7, 4.3, and 0.1, respectively. The results of the simulations show that normal liver biologically weighted dose is restricted to 4.9 Gy-Eq (CBE; liver tumour: 2.5, normal liver: 0.94); the maximum, minimum, and mean tumour weighted dose are 43.1, 7.3, and 21.8 Gy-Eq, respectively, in 40 min irradiation. In this study, we show that ¹⁰B entrapped WOW emulsion could be applied to novel intra-arterial boron delivery carrier for BNCT, and we show the possibility to apply BNCT to HCC. We can irradiate tumours as selectively and safety as possible, reducing the effects on neighbouring healthy tissues.     

Low dose of gamma irradiation enhanced boronophenylalanine uptake in head and neck carcinoma cells for boron neutron capture therapy

This study attempted to increase the boron uptake of human head and neck carcinoma SAS cells for BNCT by using a gamma dose of 0.1 Gy for combined treatment. Intracellular boron concentrations in 25 μg B/mL medium of BPA treated and BPA combined gamma-irradiation treated SAS cells were 73.8±1.73 and 95.15±1.36 ppm, respectively. After neutron irradiation, the G2/M-phase cell populations of untreated, BPA treated and BPA combined gamma-irradiation treated SAS cells were 19.31±1.71%, 52.47±2.25% and 59.19±2.63%, respectively. Experimental results indicate that the low dose gamma radiation with combination BPA treatment has the highest killing rate after neutron irradiation. Capable of significantly increasing the G2/M arrest after neutron irradiation, the combined treatment of a low dose of gamma irradiation with 25 μg B/mL medium of BPA also provided a higher killing effect for BNCT.     

A micro-PET/CT approach using O-(2-[F]fluoroethyl)-l-tyrosine in an experimental animal model of F98 glioma for BNCT

The present study focuses on a micro-PET/CT application to be used for experimental Boron Neutron Capture Therapy (BNCT), which integrates, in the same frame, micro-CT derived anatomy and PET radiotracer distribution. Preliminary results have demonstrated that ¹⁸F-fluoroethyl-tyrosine (FET)/PET allows the identification of the extent of cerebral lesions in F98 tumor bearing rat. Neutron autoradiography and α-spectrometry on axial tissues slices confirmed the tumor localization and extraction, after the administration of fructose–boronophenylalanine (BPA). Therefore, FET–PET approach can be used to assess the transport, the net influx, and the accumulation of FET, as an aromatic amino acid analog of BPA, in experimental animal model. Coregistered micro-CT images allowed the accurate morphological localization of the radiotracer distribution and its potential use for experimental BNCT.     

The interpretation of dose calculations and cell-survival measurements for the boron neutron capture therapy of brain tumours with 24 keV neurons

Monte-Carlo computer codes have been used to estimate the distribution of doses to borated and unborated tissues in head-sized phantoms when exposed to beams of 2 keV and 24 keV neutrons. For the application of such beams to boron neutron capture therapy (BNCT) these calculations show the superiority of 2 keV neutrons over 24 keV neutrons and the importance of using large-area beams. A 24 keV neutron beam has been used to irradiate HeLa cell cultures in vitro, with and without the addition of 10B, at various depths within a narrow polyethylene phantom. Survival data obtained from these experiments have been used to estimate depth-damage profiles for normal (unboronated) and tumour (boronated) brain tissues when exposed to 24 keV neutrons. A good differential between damage to normal and tumorous tissue is obtained under suitable irradiation conditions. Although lower-energy neutrons are probably preferable, these results demonstrate the possibility of using beams of 24 keV neutrons for the BNCT of brain tumours.     

Uptake of 18F-fluorocholine, 18F-fluoro-ethyl-L-tyrosine and 18F-fluoro-2-deoxyglucose in F98 gliomas in the rat

Introduction The positron emission tomography (PET) tracers ¹⁸F-fluoro-ethyl-L-tyrosine (FET), ¹⁸F-fluorocholine (N,N-dimethyl-N-[¹⁸F]fluoromethyl-2-hydroxyethylammonium (FCH]) and ¹⁸F-fluoro-2-deoxyglucose (FDG) are used in the diagnosis of brain tumours. The aim of this study was threefold: (a) to assess the uptake of the different tracers in the F98 rat glioma, (b) to evaluate the impact of blood-brain barrier (BBB) disruption and microvessel density (MVD) on tracer uptake and (c) to compare the uptake in the tumours to that in the radiation injuries (induced by proton irradiation of healthy rats) of our previous study.Methods F98 gliomas were induced in 26 rats. The uptake of FET, FCH and FDG was measured using autoradiography and correlated with histology, disruption of the BBB and MVD.Results The mean FET, FCH and FDG standardised uptake values (SUVs) in the tumour and the contralateral normal cortex (in parentheses) were 4.19±0.86 (1.32±0.26), 2.98±0.58 (0.51±0.11) and 11.02±3.84 (4.76±1.77) respectively. MVD was significantly correlated only with FCH uptake. There was a trend towards a negative correlation between the degree of BBB disruption and FCH uptake and a trend towards a positive correlation with FET uptake. The ratio of the uptake in tumours to that in the radiation injuries was 1.97 (FCH), 2.71 (FET) and 2.37 (FDG).Conclusion MVD displayed a significant effect only on FCH uptake. The degree of BBB disruption seems to affect the accumulation of FET and FCH, but not FDG. Mean tumour uptake for all tracers was significantly higher than the accumulation in radiation injuries.     

Comparison of the pharmacokinetics of 68Ga-DOTATOC and [18F]FDG in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy

Purpose The purpose of this study was to evaluate and compare, by means of dynamic PET, the pharmacokinetics of ⁶⁸Ga-DOTATOC, a tracer which reflects the expression of somatostatin receptors (SSTRs), and of [¹⁸F]FDG, a marker of tumour viability, in patients with metastatic neuroendocrine tumours (NETs) in whom ⁹⁰Y-DOTATOC therapy was planned.Materials and methods Fifteen patients (63 lesions) with confirmed metastatic NETs were enrolled in this study. Dynamic [¹⁸F]FDG and ⁶⁸Ga-DOTATOC PET scans were performed on two different days in the same week. The data analysis was based on qualitative and quantitative analysis using a two-tissue compartment model with a blood compartment and a non-compartment model based on the fractal dimension (FD). Multivariate analysis was used for evaluation of the kinetic data.Results Enhanced [¹⁸F]FDG uptake was observed in 43/63 lesions. ⁶⁸Ga-DOTATOC showed pathologically enhanced uptake in all evaluated patients and in 57/63 lesions. Discordant scintigraphic results for [¹⁸F]FDG and ⁶⁸Ga-DOTATOC were observed in 6/15 patients. Global SUV was defined as the SUV measured in the last frame (55–60 min p.i.) of the dynamic series, for each tracer. The median global SUV uptake was 7.9 for ⁶⁸Ga-DOTATOC and 4.6 for [¹⁸F]FDG. The selection of patients for ⁹⁰Y-DOTATOC therapy was based on the uptake of ⁶⁸Ga-DOTATOC. Multiple linear regression analysis was applied to determine the effect of each kinetic parameter (K ₁–k ₄, V _B) on the global SUV of both tracers. The highest positive t-ratio was found for K ₁ (receptor binding), followed by k ₃ (cellular internalisation) and V _B (fractional blood volume), when using the global ⁶⁸Ga-DOTATOC uptake (SUV) as a target variable. Analysis of the [¹⁸F]FDG data revealed the highest positive t-ratio for V _B, followed by k ₃ (phosphorylation) and K ₁ (influx). The comparison of global SUV, K ₁–k ₄ and the FD for [¹⁸F]FDG and ⁶⁸Ga-DOTATOC did not show any statistically significant correlation. The only parameter that demonstrated a significant linear correlation between the tracers was V _B.Conclusion ⁶⁸Ga-DOTATOC is a promising tool for evaluation of the expression of SSTR2 in NETs. The combination of [¹⁸F]FDG and ⁶⁸Ga-DOTATOC dynamic PET studies provides different information regarding the biological properties of lesions in patients with metastatic NETs in whom ⁹⁰Y-DOTATOC therapy is planned. While the global ⁶⁸Ga-DOTATOC uptake is influenced mostly by K ₁, the global [¹⁸F]FDG uptake is mostly influenced by V _B. Only patients with enhanced ⁶⁸Ga-DOTATOC uptake (SUV >5.0) were referred to ⁹⁰Y-DOTATOC therapy.