RESUMO
Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44+ effector memory T cells and CD69+ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.
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Terapia por Captura de Nêutron de Boro , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico , Imunoterapia , Melanoma Experimental , Animais , Camundongos , Terapia por Captura de Nêutron de Boro/métodos , Melanoma Experimental/terapia , Melanoma Experimental/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Feminino , Camundongos Endogâmicos C57BL , Linfócitos do Interstício Tumoral/imunologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Terapia Combinada , Proteína HMGB1/metabolismoRESUMO
PURPOSE: Boron neutron capture therapy (BNCT) is a tumor cell-selective particle-radiation therapy. In BNCT, administered p-boronophenylalanine (BPA) is selectively taken up by tumor cells, and the tumor is irradiated with thermal neutrons. High-LET α-particles and recoil 7Li, which have a path length of 5-9 µm, are generated by the capture reaction between 10B and thermal neutrons and selectively kill tumor cells that have uptaken 10B. Although BNCT has prolonged the survival time of malignant glioma patients, recurrences are still to be resolved. miRNAs, that are encapsulated in small extracellular vesicles (sEVs) in body fluids and exist stably may serve critical role in recurrence. In this study, we comprehensively investigated microRNAs (miRNAs) in sEVs released from post-BNCT glioblastoma cells. METHOD: Glioblastoma U87 MG cells were treated with 25 ppm of BPA in the culture media and irradiated with thermal neutrons. After irradiation, they were plated into dishes and cultured for 3 days in the 5% CO2 incubator. Then, sEVs released into the medium were collected by column chromatography, and miRNAs in sEVs were comprehensively investigated using microarrays. RESULT: An increase in 20 individual miRNAs (ratio > 2) and a decrease in 2 individual miRNAs (ratio < 0.5) were detected in BNCT cells compared with non-irradiated cells. Among detected miRNAs, 20 miRNAs were associated with worse prognosis of glioma in Kaplan Meier Survival Analysis of overall survival in TCGA. CONCLUSION: These miRNA after BNCT may proceed tumors, modulate radiation resistance, or inhibit invasion and affect the prognosis of glioma.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias Encefálicas , Vesículas Extracelulares , Glioblastoma , MicroRNAs , Terapia por Captura de Nêutron de Boro/métodos , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efeitos da radiação , MicroRNAs/metabolismo , MicroRNAs/genética , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiaçãoRESUMO
Minimally invasive boron neutron capture therapy (BNCT) is an elegant approach for cancer treatment. The highly selective and efficient deliverability of boron agents to cancer cells is the key to maximizing the therapeutic benefits of BNCT. In addition, enhancement of the frequencies to achieve boron neutron capture reaction is also significant in improving therapeutic efficacy by providing a highly concentrated boron agent in each boron nanoparticle. As the density of the thermal neutron beam remains low, it is unable to induce high-efficiency cell destruction. Herein, we report phospholipid-coated boronic oxide nanoparticles as agents for BNCT that can provide a highly concentrated boron atom in each nanoparticle. The current system exhibited inâ vitro BNCT activity seven times higher than that of commercial boron agents. Furthermore, the system could penetrate cancer spheroids deeply, efficiently suppressing thermal neutron irradiation-induced growth.
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Terapia por Captura de Nêutron de Boro , Nanopartículas , Boro , Fosfolipídeos , Compostos de Boro/uso terapêutico , ÓxidosRESUMO
Boron neutron capture therapy (BNCT) is a promising modality for cancer treatment because of its minimal invasiveness. To maximize the therapeutic benefits of BNCT, the development of efficient platforms for the delivery of boron agents is indispensable. Here, carborane-integrated immunoliposomes were prepared via an exchanging reaction to achieve HER-2-targeted BNCT. The conjugation of an anti-HER-2 antibody to carborane-integrated liposomes successfully endowed these liposomes with targeting properties toward HER-2-overexpressing human ovarian cancer cells (SK-OV3); the resulting BNCT activity toward SK-OV3 cells obtained using the current immunoliposomal system was 14-fold that of the l-BPA/fructose complex, which is a clinically available boron agent. Moreover, the growth of spheroids treated with this system followed by thermal neutron irradiation was significantly suppressed compared with treatment with the l-BPA/fructose complex.
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Boranos , Terapia por Captura de Nêutron de Boro , Humanos , Lipossomos , Terapia por Captura de Nêutron de Boro/métodos , Boro , Compostos de Boro , FrutoseRESUMO
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 closo-dodecaborate orthogonally. The accumulation of Gd-MID-BSA in tumors in CT26 tumor-bearing mice reached a maximum at 24 h after the injection, as confirmed by T1-based MRI and biodistribution analysis using inductively coupled plasma optical emission spectrometry. The concentrations of boron and gadolinium in the tumors exceeded the thresholds required for boron neutron capture therapy (BNCT) and gadolinium neutron capture therapy (GdNCT), respectively. The boron concentration ratios of tumor to blood and tumor to normal tissues satisfied the clinical criteria, indicating the reduction of undesired nuclear reactions of endogenous nuclei. The molar ratio of boron to gadolinium in the tumor was close to that of Gd-MID-BSA, demonstrating that the accumulation of Gd-MID-BSA in the tumor can be evaluated by MRI. Thermal neutron irradiation with Gd-MID-BSA resulted in significant suppression of tumor growth compared to the group injected with a boron-conjugated albumin without gadolinium (MID-BSA). The neutron irradiation with Gd-MID-BSA did not cause apparent side effects. These results demonstrate that the conjugation of gadolinium and boron within the albumin molecule offers a novel strategy for enhancing the therapeutic effect of BNCT and the potential of MRI-guided neutron capture therapy as a promising treatment for malignant tumors.
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Terapia por Captura de Nêutron de Boro , Neoplasias , Terapia por Captura de Nêutron , Camundongos , Animais , Boro , Gadolínio , Distribuição Tecidual , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Terapia por Captura de Nêutron/métodos , Imageamento por Ressonância Magnética/métodos , Terapia por Captura de Nêutron de Boro/métodos , MaleimidasRESUMO
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.
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Terapia por Captura de Nêutron de Boro , Neoplasias , Humanos , Nanogéis , Boro , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Compostos de Boro , FrutoseRESUMO
New carborane-bearing hydroxamate matrix metalloproteinase (MMP) ligands have been synthesized for boron neutron capture therapy (BNCT) with nanomolar potency against MMP-2, -9 and -13. New analogs are based on MMP inhibitor CGS-23023A, and two previously reported MMP ligands 1 (B1) and 2 (B2) were studied in vitro for BNCT activity. The boronated MMP ligands 1 and 2 showed high in vitro tumoricidal effects in an in vitro BNCT assay, exhibiting IC50 values for 1 and 2 of 2.04 × 10-2 mg/mL and 2.67 × 10-2 mg/mL, respectively. The relative killing effect of 1 to L-boronophenylalanine (BPA) is 0.82/0.27 = 3.0, and that of 2 is 0.82/0.32 = 2.6, whereas the relative killing effect of 4 is comparable to boronophenylalanine (BPA). The survival fraction of 1 and 2 in a pre-incubation boron concentration at 0.143 ppm 10B and 0.101 ppm 10B, respectively, were similar, and these results suggest that 1 and 2 are actively accumulated through attachment to the Squamous cell carcinoma (SCC)VII cells. Compounds 1 and 2 very effectively killed glioma U87 delta EGFR cells after BNCT. This study is noteworthy in demonstrating BNCT efficacy through binding to MMP enzymes overexpressed at the surface of the tumor cell without tumor cell penetration.
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Terapia por Captura de Nêutron de Boro , Glioma , Humanos , Terapia por Captura de Nêutron de Boro/métodos , Ligantes , Internalização do Vírus , Compostos de Boro/farmacologiaRESUMO
BACKGROUND: Although boron neutron capture therapy has shown excellent survival data, previous studies have shown an increase in radiation necrosis against recurrent malignant glioma. Herein, we proposed that bevacizumab may reduce radiation injury from boron neutron capture therapy by re-irradiation. We evaluated the efficacy and safety of a boron neutron capture therapy and add-on bevacizumab combination therapy in patients with recurrent malignant glioma. METHODS: Patients with recurrent malignant glioma were treated with reactor-based boron neutron capture therapy. Treatment with bevacizumab (10 mg/kg) was initiated 1-4 weeks after boron neutron capture therapy and was administered every 2-3 weeks until disease progression. Initially diagnosed glioblastomas were categorized as primary glioblastoma, whereas other forms of malignant glioma were categorized as non-primary glioblastoma. RESULTS: Twenty-five patients (14 with primary glioblastoma and 11 with non-primary glioblastoma) were treated with boron neutron capture therapy and add-on bevacizumab. The 1-year survival rate for primary glioblastoma and non-primary glioblastoma was 63.5% (95% confidence interval: 33.1-83.0) and 81.8% (95% confidence interval: 44.7-95.1), respectively. The median overall survival was 21.4 months (95% confidence interval: 7.0-36.7) and 73.6 months (95% confidence interval: 11.4-77.2) for primary glioblastoma and non-primary glioblastoma, respectively. The median progression-free survival was 8.3 months (95% confidence interval: 4.2-12.1) and 15.6 months (95% confidence interval: 3.1-29.8) for primary glioblastoma and non-primary glioblastoma, respectively. Neither pseudoprogression nor radiation necrosis were identified during bevacizumab treatment. Alopecia occurred in all patients. Six patients experienced adverse events ≥grade 3. CONCLUSIONS: Boron neutron capture therapy and add-on bevacizumab provided a long overall survival and a long progression-free survival in recurrent malignant glioma compared with previous studies on boron neutron capture therapy alone. The add-on bevacizumab may reduce the detrimental effects of boron neutron capture therapy, including pseudoprogression and radiation necrosis. Further studies of the combination therapy with a larger sample size and a randomized controlled design are warranted.
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Terapia por Captura de Nêutron de Boro , Neoplasias Encefálicas , Glioblastoma , Glioma , Lesões por Radiação , Bevacizumab/uso terapêutico , Terapia por Captura de Nêutron de Boro/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Glioma/tratamento farmacológico , Glioma/radioterapia , Humanos , Necrose/etiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Lesões por Radiação/etiologiaRESUMO
In cancer therapeutics, boron neutron capture therapy (BNCT) requires a platform for selective and efficient 10B delivery into tumor tissues for a successful treatment. However, the use of carborane, a promising candidate with high boron content and biostability, has significant limitations in the biomedical field due to its poor water-solubility and tumor-selectivity. To overcome these hurdles, we present in this study a fluorescent nano complex, combining fluorescent carborane and sodium hyaluronate for high boron concentration and tumor-selectivity. Tumor cells actively internalized the complex through binding hyaluronan to CD44, overexpressed on the tumor cell surface. Furthermore, the subcellular distribution of this complex could also be detected due to its fluorescent properties. Moreover, after thermal neutron irradiations, the complex produced excellent cytotoxicity, equal to or greater than that of the clinically-used BPA-fructose. Therefore, this novel complex could be potentially more suitable for BNCT than the boron agent.
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Boranos/uso terapêutico , Terapia por Captura de Nêutron de Boro , Ácido Hialurônico/uso terapêutico , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Ácido Hialurônico/ultraestrutura , Camundongos , Células RAW 264.7RESUMO
Boron neutron capture therapy (BNCT) is a particle radiation therapy that involves the use of a thermal or epithermal neutron beam in combination with a boron ((10)B)-containing compound that specifically accumulates in tumor. (10)B captures neutrons and the resultant fission reaction produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of high linear energy transfer (LET) radiation and therefore have marked biological effects. High-LET radiation is a potent inducer of DNA damage, specifically of DNA double-strand breaks (DSBs). The aim of the present study was to clarify the role of DNA ligase IV, a key player in the non-homologous end-joining repair pathway, in the repair of BNCT-induced DSBs. We analyzed the cellular sensitivity of the mouse embryonic fibroblast cell lines Lig4-/- p53-/- and Lig4+/+ p53-/- to irradiation using a thermal neutron beam in the presence or absence of (10)B-para-boronophenylalanine (BPA). The Lig4-/- p53-/- cell line had a higher sensitivity than the Lig4+/+ p53-/-cell line to irradiation with the beam alone or the beam in combination with BPA. In BNCT (with BPA), both cell lines exhibited a reduction of the 50 % survival dose (D 50) by a factor of 1.4 compared with gamma-ray and neutron mixed beam (without BPA). Although it was found that (10)B uptake was higher in the Lig4+/+ p53-/- than in the Lig4-/- p53-/- cell line, the latter showed higher sensitivity than the former, even when compared at an equivalent (10)B concentration. These results indicate that BNCT-induced DNA damage is partially repaired using DNA ligase IV.
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Terapia por Captura de Nêutron de Boro/efeitos adversos , Dano ao DNA , DNA Ligase Dependente de ATP/metabolismo , Reparo do DNA/efeitos da radiação , Animais , Linhagem Celular , Relação Dose-Resposta à Radiação , Camundongos , Fatores de TempoRESUMO
AIM: In this study, we investigated γH2AX foci as markers of DSBs in normal brain and brain tumor tissue in mouse after BNCT. BACKGROUND: Boron neutron capture therapy (BNCT) is a particle radiation therapy in combination of thermal neutron irradiation and boron compound that specifically accumulates in the tumor. (10)B captures neutrons and produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of extremely high linear energy transfer (LET) radiation and therefore have marked biological effects. High LET radiation causes severe DNA damage, DNA DSBs. As the high LET radiation induces complex DNA double strand breaks (DSBs), large proportions of DSBs are considered to remain unrepaired in comparison with exposure to sparsely ionizing radiation. MATERIALS AND METHODS: We analyzed the number of γH2AX foci by immunohistochemistry 30 min or 24 h after neutron irradiation. RESULTS: In both normal brain and brain tumor, γH2AX foci induced by (10)B(n,α)(7)Li reaction remained 24 h after neutron beam irradiation. In contrast, γH2AX foci produced by γ-ray irradiation at contaminated dose in BNCT disappeared 24 h after irradiation in these tissues. CONCLUSION: DSBs produced by (10)B(n,α)(7)Li reaction are supposed to be too complex to repair for cells in normal brain and brain tumor tissue within 24 h. These DSBs would be more difficult to repair than those by γ-ray. Excellent anti-tumor effect of BNCT may result from these unrepaired DSBs induced by (10)B(n,α)(7)Li reaction.
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The first BNCT antitumor effects of BNNTs toward B16 melanoma cells were demonstrated. The use of DSPE-PEG2000 was effective for preparation of the BNNT-suspended aqueous solution. BNNT-DSPE-PEG2000 accumulated in B16 melanoma cells approximately three times higher than BSH and the higher BNCT antitumor effect was observed in the cells treated with BNNT-DSPE-PEG2000 compared to those treated with BSH, indicating that BNNT-DSPE-PEG2000 would be a possible candidate as a boron delivery vehicle for BNCT.
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Antineoplásicos/administração & dosagem , Compostos de Boro/administração & dosagem , Terapia por Captura de Nêutron de Boro/métodos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/radioterapia , Nanotubos , Animais , Antineoplásicos/química , Compostos de Boro/química , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Nanotubos/química , Nêutrons , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/radioterapiaRESUMO
Although boron neutron capture therapy (BNCT) causes minor damage to normal cells owing to the nuclear reactions induced by neutrons with major elements of tissues such as hydrogen and nitrogen, it is useful to estimate the accurate exposure dose for radiation protection. This study aims to estimate the contribution of internal exposure in radiation exposure dose for BNCT. The study was performed by referring to clinical studies at a reactor-based BNCT facility on the basis of computational dosimetry. Five irradiation regions of head and neck were selected for the estimation. The results suggest that external exposure occurred primarily in and around the irradiation field. Furthermore, during the exposure dose estimation in BNCT, internal exposure was found to be not negligible, implying that the irradiation regions in treatment planning must be considered for avoiding damage to certain critical organs that are susceptible to internal exposure.
Assuntos
Terapia por Captura de Nêutron de Boro , Terapia por Captura de Nêutron de Boro/métodos , Humanos , Dosagem Radioterapêutica , Nêutrons , Doses de Radiação , Radiometria/métodos , Proteção Radiológica/métodos , Exposição à Radiação/análise , Planejamento da Radioterapia Assistida por Computador/métodos , Método de Monte Carlo , Neoplasias de Cabeça e Pescoço/radioterapia , Imagens de Fantasmas , Simulação por ComputadorRESUMO
BACKGROUND: In Japan, the clinical treatment of boron neutron capture therapy (BNCT) has been applied to unresectable, locally advanced, and recurrent head and neck carcinomas using an accelerator-based neutron source since June of 2020. Considering the increase in the number of patients receiving BNCT, efficiency of the treatment planning procedure is becoming increasingly important. Therefore, novel and rapid dose calculation algorithms must be developed. We developed a novel algorithm for calculating neutron flux, which comprises of a combination of a Monte Carlo (MC) method and a method based on the removal-diffusion (RD) theory (RD calculation method) for the purpose of dose calculation of BNCT. PURPOSE: We present the details of our novel algorithm and the verification results of the calculation accuracy based on the MC calculation result. METHODS: In this study, the "MC-RD" calculation method was developed, wherein the RD calculation method was used to calculate the thermalization process of neutrons and the MC method was used to calculate the moderation process. The RD parameters were determined by MC calculations in advance. The MC-RD calculation accuracy was verified by comparing the results of the MC-RD and MC calculations with respect to the neutron flux distributions in each of the cubic and head phantoms filled with water. RESULTS: Comparing the MC-RD calculation results with those of MC calculations, it was found that the MC-RD calculation accurately reproduced the thermal neutron flux distribution inside the phantom, with the exception of the region near the surface of the phantom. CONCLUSIONS: The MC-RD calculation method is useful for the evaluation of the neutron flux distribution for the purpose of BNCT dose calculation, except for the region near the surface.
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Algoritmos , Terapia por Captura de Nêutron de Boro , Método de Monte Carlo , Nêutrons , Planejamento da Radioterapia Assistida por Computador , Terapia por Captura de Nêutron de Boro/métodos , Nêutrons/uso terapêutico , Planejamento da Radioterapia Assistida por Computador/métodos , Difusão , Dosagem Radioterapêutica , Imagens de Fantasmas , HumanosRESUMO
From the viewpoints of the advantage depths (ADs), peak tumor dose and skin dose, we evaluated the effect on the dose distribution of neutron beam properties, namely the ratio between thermal and epithermal neutron fluxes (thermal/epithermal ratio), fast neutron component and γ-ray component. Several parameter surveys were conducted with respect to the beam properties of neutron sources for boron neutron capture therapy assuming boronophenylalanine as the boron agent using our dose calculation tool, called SiDE. The ADs decreased by 3% at a thermal/epithermal ratio of 20-30% compared with the current recommendation of 5%. The skin dose increased with the increasing thermal/epithermal ratio, reaching a restricted value of 14 Gyeq at a thermal/epithermal ratio of 48%. The fast neutron component was modified using two different models, namely the 'linear model', in which the fast neutron intensity decreases log-linearly with the increasing neutron energy, and the 'moderator thickness (MT) model', in which the fast neutron component is varied by adjusting the MT in a virtual beam shaping assembly. Although a higher fast neutron component indicated a higher skin dose, the increment was <10% at a fast neutron component of <1 × 10-12 Gy cm2 for both models. Furthermore, in the MT model, the epithermal neutron intensity at a fast neutron component of 6.8 × 10-13 Gy cm2 was 41% higher compared with that of 2 × 10-13 Gy cm2. The γ-ray component also caused no significant disadvantages up to several times larger compared with the current recommendation.
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Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer.
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Terapia por Captura de Nêutron de Boro , Glucose , Neoplasias Pancreáticas , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Humanos , Glucose/metabolismo , Linhagem Celular Tumoral , Animais , Compostos de Boro/química , Compostos de Boro/uso terapêutico , Boro/química , Feminino , Camundongos NusRESUMO
With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.
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Terapia por Captura de Nêutron de Boro , Vesículas Extracelulares , Terapia por Captura de Nêutron de Boro/métodos , Animais , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Camundongos , Humanos , Boranos/química , Boro/química , Compostos de Boro/química , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
In boron neutron capture therapy (BNCT), treatment planning images are acquired in the recumbent position. However, treatment is occasionally performed in the sitting position. For BNCT treatment planning, we investigated the usability of cone-beam computed tomography (CBCT) images using digital radiography equipment that allows imaging in the sitting position. The dose calculation results in both CBCT and fan beam CT were in good agreement. This method will eliminate the posture difference between planning and treatment.
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Terapia por Captura de Nêutron de Boro , Intensificação de Imagem Radiográfica , Terapia por Captura de Nêutron de Boro/métodos , Postura Sentada , Imagens de Fantasmas , Tomografia Computadorizada de Feixe Cônico , Planejamento da Radioterapia Assistida por Computador/métodosRESUMO
As function preservation cancer therapy, targeted radiation therapies have been developed for the quality of life of cancer patients. However, preclinical animal studies evaluating the safety and efficacy of targeted radiation therapy is challenging from the viewpoints of animal welfare and animal protection, as well as the management of animal in radiation-controlled areas under the regulations. We fabricated the human 3D oral cancer model that considers the time axis of the follow up in cancer treatment. Therefore, in this study, the 3D model with human oral cancer cells and normal oral fibroblasts was treated based on clinical protocol. After cancer treatment, the histological findings of the 3D oral cancer model indicated the clinical correlation between tumor response and surrounding normal tissue. This 3D model has potential as a tool for preclinical studies alternative to animal studies.
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BACKGROUND/AIM: To investigate the long-term influence of head-neutron irradiation on mice spleens, post-radiation late effects were examined in three types of mice: Balb/c and severe combined immunodeficiency (SCID) mice, which have high radio-sensitivities, and C3H mice. MATERIALS AND METHODS: Neutron irradiation was performed with the neutron beam of the Kyoto University Research Reactor. Survival fractions and the change in spleen size after head-neutron irradiation were investigated in three different types of mice. Physical condition after neutron irradiation was observed for eighteen months. RESULTS: The onset of primary splenic malignant lymphoma was recognized in many of the Balb/c mice 18 months after head-neutron irradiation. Eight months after head-neutron irradiation, many SCID mice developed an abscess in the part exposed to radiation and spleen swelling. The swollen spleen of SCID mice had hematopoiesis from the marrow. CONCLUSION: Low energy head-neutron irradiation damages immune organs in radiosensitive SCID and Balb/c mice. A combination of boron neutron capture therapy and immunotherapy may be less toxic than low-energy neutron-irradiation alone.