RESUMEN
To optimize the preparation methods for liposomes encapsulating mercaptoundecahydrododecaborate (BSH), we examined BSH and lipid concentrations that increased the boron content in liposomes. We improved the BSH encapsulation efficiency and boron content of the liposomes from 4.2 to 45.9 % and 9.5-54.3 µg, respectively, by changing the lipid concentration from 10 to 150 mg/mL. Notably, the boron content increased significantly from 26.2 µg to 326.3 µg at a constant lipid concentration of 30 mg/mL with increased BSH concentrations.
Asunto(s)
Borohidruros/administración & dosificación , Liposomas , Compuestos de Sulfhidrilo/administración & dosificación , Animales , Terapia por Captura de Neutrón de Boro/métodos , RatonesRESUMEN
Purpose: To evaluate the efficacy of boron neutron capture therapy (BNCT) for a heterotopic U87 glioblastoma model in SCID mice using boron phenylalanine (BPA), sodium borocaptate (BSH) and liposomal BSH as boron compounds at a unique, accelerator-based neutron source.Materials and methods: Glioblastoma models were obtained by subcutaneous implantation of U87 cells in the right thighs of SCID mice before administration of 350 mg/kg of BPA (BPA-group), 100 mg/kg of BSH (BSH-group) or 100 mg/kg of BSH in PEGylated liposomes (liposomal BSH-group) into the retroorbital sinus. Liposomes were prepared by reverse-phase evaporation. Neutron irradiation was carried out at a proton accelerator with a lithium target developed for BNCT at the Budker Institute of Nuclear Physics, Novosibirsk, Russian Federation. A proton beam current integral of 3 mA/h and energy of 2.05 MeV were used for neutron generation.Results: Boron compound accumulation in tumor tissues at the beginning of irradiation was higher in the BPA group, followed by the Liposomal BSH and BSH groups. Tumor growth was significantly slower in all irradiated mice from the 7th day after BNCT compared to untreated controls (p < .05). Tumor growth in all treated groups showed no large variation, apart from the Irradiation only group and the BPA group on the 7th day after BNCT. The overall trend of tumor growth was clear and the differences between treatment groups became significant from the 50th day after BNCT. Tumor growth was significantly slower in the Liposomal BSH group compared to the Irradiation only group on the 50th (p = .012), 53rd (p = .005), and the 57th (p = .021) days after treatment. Tumor growth in the Liposomal BSH group was significantly different from that in the BPA group on the 53rd day after BNCT (p = .021) and in the BSH group on the 50th (p = .024), 53rd (p = .015), and 57th (p = .038) days after BNCT. Skin reactions in the form of erosions and ulcers in the tumor area developed in treated as well as untreated animals with further formation of fistulas and necrotic decay cavities in most irradiated mice.Conclusions: We observed a tendency of BNCT at the accelerator-based neutron source to reduce or suspend the growth of human glioblastoma in immunodeficient animals. Liposomal BSH showed better long-term results compared to BPA and non-liposomal BSH. Further modifications in liposomal boron delivery are being studied to improve treatment outcomes.
Asunto(s)
Borohidruros/uso terapéutico , Compuestos de Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro/métodos , Glioblastoma/radioterapia , Neutrones/uso terapéutico , Fenilalanina/análogos & derivados , Compuestos de Sulfhidrilo/uso terapéutico , Animales , Borohidruros/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Modelos Animales de Enfermedad , Glioblastoma/patología , Humanos , Liposomas , Ratones , Ratones SCID , Fenilalanina/uso terapéutico , Proyectos Piloto , Compuestos de Sulfhidrilo/administración & dosificaciónRESUMEN
The uptake of (10)boron by tumor cells plays an important role for cell damage in boron neutron capture therapy (BNCT). CD133 is frequently expressed in the membrane of glioma stem cells (GSCs), resistant to radiotherapy and chemotherapy, and represents a potential therapeutic target. To increase (10)boron uptake in GSCs, we created a polyamido amine dendrimer, conjugated CD133 monoclonal antibodies, encapsulating mercaptoundecahydrododecaborate (BSH) in void spaces, and monitored the uptake of the bioconjugate nanoparticles by GSCs in vitro and in vivo. Fluorescence microscopy showed the specific uptake of the bioconjugate nanoparticles by CD133-positive GSCs. Treatment with the biconjugate nanoparticles resulted in a significant lethal effect after neutron radiation due to efficient and CD133-independent cellular targeting and uptake in CD133-expressing GSCs. A significantly longer survival occurred in combination with the biconjugate nanoparticles and BSH compared with BSH alone in human intracranial GBM models employing CD133-positive GSCs xenografts. Our data demonstrated that this bioconjugate nanoparticle targets human CD133-positive GSCs and is a potential boron agent in BNCT.
Asunto(s)
Antígeno AC133/antagonistas & inhibidores , Antineoplásicos Inmunológicos/uso terapéutico , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/radioterapia , Membrana Celular/efectos de la radiación , Glioma/radioterapia , Células Madre Neoplásicas/efectos de la radiación , Antígeno AC133/metabolismo , Animales , Antineoplásicos Inmunológicos/administración & dosificación , Borohidruros/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Membrana Celular/metabolismo , Dendrímeros/química , Glioma/tratamiento farmacológico , Glioma/mortalidad , Glioma/patología , Humanos , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microscopía Fluorescente , Nanoconjugados/química , Células Madre Neoplásicas/metabolismo , Compuestos de Sulfhidrilo/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To determine the influence of buthionine sulfoximine (BSO) on boron biodistribution after sulfhydryl borane (BSH) administration for boron neutron capture therapy, the effectiveness of the combination of BSO with sulfhydril- (BSH) and non-sulfhydril (B12H12 and BNH3) boron compounds, and the interval between BSO and BSH administration, the retention of boron in tissues have been evaluated using a 9L rat tumor model. Simultaneous administration of BSH and BSO showed significantly higher boron accumulation compared to that without BSO, however there was no difference in tissue boron level between B12H12 and BNH3 administration with BSO or without BSO. The longer interval (6h) between BSH and BSO administration related to the highest boron concentration in the brain and subcutaneous tumors compared to shorter intervals (0.5, 3h). Boron concentration in subcutaneous and brain tumors was maintained for 6 and 12h after the administration of BSH following BSO pretreatment.
Asunto(s)
Borohidruros/administración & dosificación , Borohidruros/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/metabolismo , Butionina Sulfoximina/administración & dosificación , Butionina Sulfoximina/farmacocinética , Premedicación/métodos , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/farmacocinética , Animales , Neoplasias Encefálicas/radioterapia , Sinergismo Farmacológico , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Especificidad de Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Distribución Tisular/efectos de los fármacosRESUMEN
A 63-year-old man with multiple HCC in his left liver lobe was enrolled as the first patient in a pilot study of boron neutron capture therapy (BNCT) involving the selective intra-arterial infusion of a (10)BSH-containing water-in-oil-in-water emulsion ((10)BSH-WOW). The size of the tumorous region remained stable during the 3 months after the BNCT. No adverse effects of the BNCT were observed. The present results show that (10)BSH-WOW can be used as novel intra-arterial boron carriers during BNCT for HCC.
Asunto(s)
Borohidruros/administración & dosificación , Terapia por Captura de Neutrón de Boro/métodos , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Compuestos de Sulfhidrilo/administración & dosificación , Borohidruros/química , Carcinoma Hepatocelular/diagnóstico , Emulsiones/administración & dosificación , Emulsiones/química , Humanos , Inyecciones Intraarteriales , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Aceites/química , Proyectos Piloto , Compuestos de Sulfhidrilo/química , Resultado del Tratamiento , Agua/químicaRESUMEN
Sodium mercaptoundecahydro-closo-dodecaborate (BSH) is being investigated clinically for BNCT. We examined the biodistribution of BSH and BPA administered jointly in different proportions in the hamster cheek pouch oral cancer model. The 3 assayed protocols were non-toxic, and showed preferential tumor boron uptake versus precancerous and normal tissue and therapeutic tumor boron concentration values (70-85ppm). All 3 protocols warrant assessment in BNCT studies to contribute to the knowledge of (BSH+BPA)-BNCT radiobiology for head and neck cancer and optimize therapeutic efficacy.
Asunto(s)
Borohidruros/administración & dosificación , Borohidruros/farmacocinética , Compuestos de Boro/administración & dosificación , Compuestos de Boro/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/radioterapia , Fenilalanina/análogos & derivados , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/farmacocinética , Animales , Mejilla , Cricetinae , Combinación de Medicamentos , Mesocricetus , Tasa de Depuración Metabólica , Especificidad de Órganos , Fenilalanina/administración & dosificación , Fenilalanina/farmacocinética , Dosificación Radioterapéutica , Distribución Tisular , Resultado del TratamientoRESUMEN
BACKGROUND: Boron neutron capture therapy (BNCT) is a cell-selective radiation therapy that uses the alpha particles and lithium nuclei produced by the boron neutron capture reaction. BNCT is a relatively safe tool for treating multiple or diffuse malignant tumors with little injury to normal tissue. The success or failure of BNCT depends upon the 10B compound accumulation within tumor cells and the proximity of the tumor cells to the body surface. To extend the therapeutic use of BNCT from surface tumors to visceral tumors will require 10B compounds that accumulate strongly in tumor cells without significant accumulation in normal cells, and an appropriate delivery method for deeper tissues.Hemagglutinating Virus of Japan Envelope (HVJ-E) is used as a vehicle for gene delivery because of its high ability to fuse with cells. However, its strong hemagglutination activity makes HVJ-E unsuitable for systemic administration.In this study, we developed a novel vector for 10B (sodium borocaptate: BSH) delivery using HVJ-E and cationized gelatin for treating multiple liver tumors with BNCT without severe adverse events. METHODS: We developed cationized gelatin conjugate HVJ-E combined with BSH (CG-HVJ-E-BSH), and evaluated its characteristics (toxicity, affinity for tumor cells, accumulation and retention in tumor cells, boron-carrying capacity to multiple liver tumors in vivo, and bio-distribution) and effectiveness in BNCT therapy in a murine model of multiple liver tumors. RESULTS: CG-HVJ-E reduced hemagglutination activity by half and was significantly less toxic in mice than HVJ-E. Higher 10B concentrations in murine osteosarcoma cells (LM8G5) were achieved with CG-HVJ-E-BSH than with BSH. When administered into mice bearing multiple LM8G5 liver tumors, the tumor/normal liver ratios of CG-HVJ-E-BSH were significantly higher than those of BSH for the first 48 hours (p < 0.05). In suppressing the spread of tumor cells in mice, BNCT treatment was as effective with CG-HVJ-E-BSH as with BSH containing a 35-fold higher 10B dose. Furthermore, CG-HVJ-E-BSH significantly increased the survival time of tumor-bearing mice compared to BSH at a comparable dosage of 10B. CONCLUSION: CG-HVJ-E-BSH is a promising strategy for the BNCT treatment of visceral tumors without severe adverse events to surrounding normal tissues.
Asunto(s)
Borohidruros/administración & dosificación , Terapia por Captura de Neutrón de Boro/métodos , Cápside , Carcinoma/radioterapia , Gelatina/farmacología , Neoplasias Hepáticas/radioterapia , Virus Sendai , Compuestos de Sulfhidrilo/administración & dosificación , Animales , Cápside/química , Carcinoma/patología , Cationes/farmacología , Línea Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Femenino , Gelatina/química , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos C3H , Trasplante de Neoplasias , Virus Sendai/química , Virus Sendai/ultraestructura , Resultado del TratamientoRESUMEN
BACKGROUND: To achieve potent tumor-selective antitumor efficacy by boron neutron capture therapy (BNCT), it is important to have a significant differential uptake of 10B between tumor cells and normal cells. This should enable BNCT to reduce damage to normal tissues compared with other radiation therapies. OBJECTIVE: To augment the therapeutic efficacy of BNCT, we used transferrin-conjugated polyethylene glycol (PEG) (TF-PEG) liposome encapsulating sodium borocaptate and Iomeprol, an iodine contrast agent, with intratumoral convection-enhanced delivery (CED) in a rat glioma tumor model. METHODS: The in vitro (10)B concentration of F98 rat glioma cells was determined by inductively coupled plasma atomic emission spectrometry after incubation with either TF-PEG or PEG liposomes. For in vivo biodistribution studies, (10)B concentrations within blood, normal brain tissue, and intracerebrally transplanted F98 cells were measured with inductively coupled plasma-atomic emission spectrometry after CED of the compounds, and computed tomography was performed at selected time intervals. RESULTS: (10)B concentrations of F98 cultured glioma cells in vitro 6 hours after exposure to PEG and TF-PEG liposome were 16.1 and 51.9 ng (10)B/10(6) cells, respectively. (10)B concentrations in F98 glioma tissue 24 hours after CED were 22.5 and 82.2 µg/g, by PEG and TF-PEG liposome, respectively, with lower (10)B concentrations in blood and normal brain. Iomeprol provided vivid and stable enhanced computed tomography imaging of the transplanted tumor even 72 hours after CED by TF-PEG liposome. Conversely, tissue enhancement had already washed out at 24 hours after CED of the PEG liposomes. CONCLUSION: The combination of TF-PEG liposome encapsulating sodium borocaptate and Iomeprol and intratumoral CED enables not only a precise and potent targeting of boron delivery to the tumor tissue, but also the ability to follow the trace of boron delivery administered intratumorally by real-time computed tomography.
Asunto(s)
Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/radioterapia , Sistemas de Liberación de Medicamentos/métodos , Glioma/diagnóstico por imagen , Glioma/radioterapia , Tomografía Computarizada por Rayos X , Animales , Borohidruros/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Medios de Contraste/administración & dosificación , Glioma/tratamiento farmacológico , Yodo/administración & dosificación , Yopamidol/administración & dosificación , Yopamidol/análogos & derivados , Liposomas , Masculino , Ratas , Ratas Endogámicas F344 , Compuestos de Sulfhidrilo/administración & dosificación , Tomografía Computarizada por Rayos X/métodos , Transferrina/administración & dosificación , Células Tumorales CultivadasRESUMEN
Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce α-particles (10B[n,α] Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these compounds, designated H2TBP, H2TCP, and H2DCP, have been evaluated in the present study. The goals were two-fold. First, to determine their biodistribution following intracerebral (i.c.) administration by short term (30 min) convection enhanced delivery (CED) or sustained delivery over 24 h by Alzet™ osmotic pumps to F98 glioma bearing rats. Second, to determine the efficacy of H2TCP and H2TBP as boron delivery agents for BNCT in F98 glioma bearing rats. Tumor boron concentrations immediately after i.c. pump delivery were high and they remained so at 24 h. The corresponding normal brain concentrations were low and the blood and liver concentrations were undetectable. Based on these data, therapy studies were initiated at the Massachusetts Institute of Technology (MIT) Research Reactor (MITR) with H2TCP and H2TBP 24 h after CED or pump delivery. Mean survival times (MST) ± standard deviations of animals that had received H2TCP or H2TBP, followed by BNCT, were of 35 ± 4 and 44 ± 10 days, compared to 23 ± 3 and 27 ± 3 days, respectively, for untreated and irradiated controls. However, since the tumor boron concentrations of the carboranylporphyrins were 3-5× higher than intravenous (i.v.) boronophenylalanine (BPA), we had expected that the MSTs would have been greater. Histopathologic examination of brains of BNCT treated rats revealed that there were large numbers of porphyrin-laden macrophages, as well as extracellular accumulations of porphyrins, indicating that the seemingly high tumor boron concentrations did not represent the true tumor cellular uptake. Nevertheless, our data are the first to show that carboranyl porphyrins can be used as delivery agents for BNCT of an experimental brain tumor. Based on these results, we now are in the process of synthesizing and evaluating carboranylporphyrins that could have enhanced cellular uptake and improved therapeutic efficacy.
Asunto(s)
Borohidruros/administración & dosificación , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Porfirinas/farmacocinética , Animales , Convección , Femenino , Ratones , Ratones Endogámicos C57BL , Ratas , Distribución TisularRESUMEN
In boron neutron capture therapy, the absorbed dose from the (10)B(n,alpha)(7)Li reaction depends on the (10)B concentration and (10)B distribution in the irradiated volume. Thus compounds used in BNCT should have tumor-specific uptake and low accumulation in normal tissues. This study compares in a mouse model the (10)B uptake in different organs as delivered by l-para-boronophenylalanine (BPA, 700 mg/kg body weight, i.p.) and/or sodium mercaptoundecahydro-closo-dodecaborate (BSH, 200 mg/kg body weight, i.p). After BSH injection, the (10)B concentration was high in kidneys (20 +/- 12 microg/g) and liver (20 +/- 12 microg/g) but was low in brain (1.0 +/- 0.8 microg/g) and muscle (1.9 +/- 1.2 microg/g). After BPA injection, the (10)B concentration was high in kidneys (38 +/- 25 microg/g) and spleen (17 +/- 8 microg/g) but low in brain (5 +/- 3 microg/g). After combined BPA and BSH injection, the effect on the absolute (10)B concentration was additive in all organs. The ratio of the (10)B concentrations in tissues and blood differed significantly for the two compounds depending on the compound combination, which implies a different uptake profile for normal organs.
Asunto(s)
Borohidruros/administración & dosificación , Compuestos de Boro/administración & dosificación , Terapia por Captura de Neutrón de Boro , Boro/farmacocinética , Boro/uso terapéutico , Fenilalanina/análogos & derivados , Compuestos de Sulfhidrilo/administración & dosificación , Animales , Borohidruros/farmacocinética , Borohidruros/uso terapéutico , Boro/química , Compuestos de Boro/farmacocinética , Compuestos de Boro/uso terapéutico , Quimioterapia Combinada , Inyecciones , Isótopos , Masculino , Ratones , Especificidad de Órganos , Fenilalanina/administración & dosificación , Fenilalanina/farmacocinética , Fenilalanina/uso terapéutico , Compuestos de Sulfhidrilo/farmacocinética , Compuestos de Sulfhidrilo/uso terapéutico , Distribución TisularRESUMEN
Over the past 25 years research on boron neutron capture therapy (BNCT) has progressed relatively slowly but steadily with the greatest progress in the field of clinical studies. These specifically have included the use of BNCT to treat a variety of malignancies other than high grade gliomas and melanomas. However, there are a number of key areas where little, if any, significant progress has been made. First and foremost among these has been the lack of new boron delivery agents. Improvement in drug delivery and the development of the best dosing paradigms for both boronophenylalanine (BPA) and sodium borocaptate (BSH) are of major importance and these still have not been optimized. Dosimetry for BNCT is still imprecise and is based on treating to normal tissue tolerance, based on blood boron values, rather than any real-time information on the boron content of the residual tumor that is to be irradiated. Another major problem has been the total dependence on nuclear reactors as neutron sources for BNCT. However, this will change in the near future when a clinically useful accelerator comes into use in 2009. Like it or not, in order to gain the credibility of a broad community of physicians who treat brain tumor patients, there will have to be a randomized clinical trial. Finally, BNCT will have to compete with new therapeutic approaches that are less costly and more effective for the treatment of brain tumors. These challenges notwithstanding, BNCT can fill an important niche for those malignancies, whether primary or recurrent, for which there is currently no effective therapy.
Asunto(s)
Terapia por Captura de Neutrón de Boro/tendencias , Animales , Borohidruros/administración & dosificación , Borohidruros/uso terapéutico , Compuestos de Boro/administración & dosificación , Compuestos de Boro/uso terapéutico , Neoplasias Encefálicas/radioterapia , Neutrones Rápidos/uso terapéutico , Glioma/radioterapia , Humanos , Reactores Nucleares , Fenilalanina/administración & dosificación , Fenilalanina/análogos & derivados , Fenilalanina/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Planificación de la Radioterapia Asistida por Computador , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/uso terapéuticoRESUMEN
The effect of administration mode of L-BPA and BSH on the biodistribution in the melanoma-bearing hamsters was investigated. In single intravenous (i.v.) administration, BSH (100 mg BSH/kg) showed no significant retention of (10)B in all the tissues, including tumors, while long-term retention of (10)B in the tumor, muscle and brain was observed with L-BPA (500 mg BPA/kg). The dose escalation of L-BPA and the simultaneous single administration of L-BPA and BSH were not so effective at increasing boron accumulation in tumor after bolus i.v. injection. The boron concentration in tumor was 41 microg B/g after single bolus i.v. injection even at the dose of 1000 mg BPA/kg. In contrast, two sequential bolus i.v. injections of l-BPA with the dose of 500 mg BPA/kg each was found to be effective at increasing (10)B accumulation in the tumor; the maximum (10)B concentration in the tumor reached 52 microg B/g at 3 h after the second i.v. injection.
Asunto(s)
Borohidruros/administración & dosificación , Borohidruros/farmacocinética , Compuestos de Boro/administración & dosificación , Compuestos de Boro/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Melanoma Experimental/metabolismo , Melanoma Experimental/radioterapia , Fenilalanina/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/farmacocinética , Animales , Borohidruros/uso terapéutico , Boro/farmacocinética , Compuestos de Boro/uso terapéutico , Cricetinae , Femenino , Isótopos/farmacocinética , Mesocricetus , Fenilalanina/administración & dosificación , Fenilalanina/farmacocinética , Fenilalanina/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Compuestos de Sulfhidrilo/uso terapéutico , Distribución TisularRESUMEN
BNCT requires high concentration and selective delivery of (10)B to the tumor cell. To improve the drug delivery in BNCT, we conducted a study by devising TPLB. We administrated three types of boron delivery systems: BSH, PLB and TPLB, to Oral SCC bearing mice. Results confirmed that (10)B concentration is higher in the TPLB group than in the BSH group and that TPLB is significantly effective as boron delivery system.
Asunto(s)
Borohidruros/administración & dosificación , Borohidruros/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/radioterapia , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/farmacocinética , Animales , Borohidruros/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Liposomas , Masculino , Ratones , Ratones Endogámicos BALB C , Polietilenglicoles , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Compuestos de Sulfhidrilo/uso terapéutico , TransferrinaRESUMEN
Nanoparticles are effective of delivering cargo into cells. Here, sodium borocaptate (BSH) was encapsulated in liposomes composed of nickel lipid, and anti-epidermal growth factor receptor (EGFR) antibodies were conjugated to the liposomes using the antibody affinity motif of protein A (ZZ) as an adaptor (immunoliposomes). The immunoliposomes were used to deliver BSH into EGFR-overexpressing glioma cells. Immunohistochemical analysis using an anti-BSH monoclonal antibody revealed that BSH was delivered effectively into the cells but not into EGFR-deficient glioma or primary astrocytes. In an animal model of brain tumors, both the liposomes and the BSH were only observed in the tumor. Moreover, the efficiency of (10)B's delivery into glioma cells was confirmed by inductively coupled plasma-atomic emission spectrometry (ICP-AES) both in vitro and in vivo. The results suggest that this system utilizing immunoliposomes provides an effective means of delivering (10)B into glioma cells in boron neutron capture therapy (BNCT).
Asunto(s)
Anticuerpos Monoclonales/farmacología , Borohidruros/administración & dosificación , Borohidruros/uso terapéutico , Receptores ErbB/inmunología , Glioma/tratamiento farmacológico , Proteína Estafilocócica A/química , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/uso terapéutico , Secuencias de Aminoácidos , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Glioma/patología , Humanos , Inmunohistoquímica , Liposomas , Ratones , Ratones Desnudos , Ratas , Espectrofotometría Atómica , Factores de Tiempo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced.
Asunto(s)
Borohidruros/farmacología , Terapia por Captura de Neutrón de Boro/métodos , Boro/metabolismo , Butionina Sulfoximina/farmacología , Neoplasias Experimentales/radioterapia , Compuestos de Sulfhidrilo/farmacología , Animales , Borohidruros/administración & dosificación , Butionina Sulfoximina/administración & dosificación , Isótopos/metabolismo , Masculino , Trasplante de Neoplasias , Ratas , Ratas Endogámicas F344 , Compuestos de Sulfhidrilo/administración & dosificaciónRESUMEN
OBJECT: Boron neutron capture therapy (BNCT) requires selective delivery of a high concentration of boron-10 ((10)B) to tumor tissue. To improve a drug delivery in BNCT, we devised transferrin-conjugated polyethylene-glycol liposome encapsulating sodium borocaptate (TF-PEG-BSH). METHODS: (10)B concentrations of U87Delta human glioma cells from three boron delivery systems (BDS) (bare BSH, PEG-BSH, and TF-PEG-BSH) were analyzed in vitro by use of inductively coupled plasma-atomic emission spectrometry (ICP-AES). A colony-forming assay (CFA) was performed using this cell line with the three BDS and neutron irradiation. Subcellular localization of BSH in tumor cells was analyzed in vitro by immunocytochemistry using monoclonal antibodies raised for BSH. Brain tumor models were made and the (10)B concentrations of the tumor, blood, and normal brain from each BDS were analyzed in vivo by use of ICP-AES. The tumor-to-blood and the tumor-to-normal brain ratios were evaluated. BNCT for the brain tumor models was performed and survival was analyzed. RESULTS: In CFA, TF-PEG-BSH showed the most prominent effects by neutron irradiation among the three BDS. TF-PEG-BSH showed highly selective and highly efficient (10)B delivery in tumor tissue. The survival rate in the treatment experiment was best in the TF-PEG-BSH group. Immunocytochemically, TF-PEG-BSH delivered BSH efficiently not only into the cytoplasm but also into the nucleus. CONCLUSION: TF-PEG-BSH is a potent BDS for BNCT not only in terms of delivering a high concentration of (10)B into tumor tissue, but also the selective delivery of (10)B into the tumor cells.
Asunto(s)
Borohidruros/administración & dosificación , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/radioterapia , Sistemas de Liberación de Medicamentos , Glioma/radioterapia , Compuestos de Sulfhidrilo/administración & dosificación , Animales , Borohidruros/farmacocinética , Humanos , Liposomas/administración & dosificación , Masculino , Ratones , Ratones Desnudos , Polietilenglicoles/administración & dosificación , Espectrofotometría Atómica , Compuestos de Sulfhidrilo/farmacocinética , Distribución Tisular , Transferrina/administración & dosificaciónRESUMEN
PURPOSE: To investigate bystander mutagenic effects induced by alpha-particles during boron neutron capture therapy, we mixed cells that were electroporated with borocaptate sodium (BSH), which led to the accumulation of (10)B inside the cells, and cells that did not contain the boron compound. The BSH-containing cells were irradiated with alpha-particles produced by the 10B(n,alpha)7Li reaction, whereas cells without boron were affected only by the 1H(n,gamma)2H and 14N(n,rho)14C reactions. METHODS AND MATERIALS: The lethality and mutagenicity measured by the frequency of mutations induced in the hypoxanthine-guanine phosphoribosyltransferase locus were examined in Chinese hamster ovary cells irradiated with neutrons (Kyoto University Research Reactor: 5 MW). Neutron irradiation of 1:1 mixtures of cells with and without BSH resulted in a survival fraction of 0.1, and the cells that did not contain BSH made up 99.4% of the resulting cell population. The molecular structures of the mutations were determined using multiplex polymerase chain reactions. RESULTS: Because of the bystander effect, the frequency of mutations increased in the cells located nearby the BSH-containing cells compared with control cells. Molecular structural analysis indicated that most of the mutations induced by the bystander effect were point mutations and that the frequencies of total and partial deletions induced by the bystander effect were less than those induced by the original neutron irradiation. CONCLUSION: These results suggested that in boron neutron capture therapy, the mutations caused by the bystander effect and those caused by the original neutron irradiation are induced by different mechanisms.
Asunto(s)
Borohidruros/administración & dosificación , Terapia por Captura de Neutrón de Boro , Efecto Espectador , Hipoxantina Fosforribosiltransferasa/genética , Mutación/genética , Compuestos de Sulfhidrilo/administración & dosificación , Animales , Borohidruros/metabolismo , Boro/metabolismo , Células CHO/metabolismo , Células CHO/efectos de la radiación , Cricetinae , Cricetulus , Electroporación , Hipoxantina Fosforribosiltransferasa/efectos de la radiación , Isótopos/metabolismo , Neutrones/uso terapéutico , Compuestos de Sulfhidrilo/metabolismoRESUMEN
PURPOSE: To evaluate GB-10-encapsulating transferrin (TF)-pendant-type polyethyleneglycol (PEG) liposomes as tumor-targeting (10)B-carriers for boron neutron capture therapy. METHODS AND MATERIALS: A free mercaptoundecahydrododecaborate-(10)B (BSH) or decahydrodecaborate-(10)B (GB-10) solution, bare liposomes, PEG liposomes, or TF-PEG liposomes were injected into SCC VII tumor-bearing mice, and (10)B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Meanwhile, tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all intratumor proliferating cells, then injected with these (10)B-carriers containing BSH or GB-10 in the same manner. Right after thermal neutron irradiation, the response of quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The frequency in the total tumor cells was determined from the BrdU nontreated tumors. RESULTS: Transferrin-PEG liposomes showed a prolonged retention in blood circulation, low uptake by reticuloendothelial system, and the most enhanced accumulation of (10)B in solid tumors. In general, the enhancing effects were significantly greater in total cells than Q cells. In both cells, the enhancing effects of GB-10-containing (10)B-carriers were significantly greater than BSH-containing (10)B-carriers, whether loaded in free solution or liposomes. In both cells, whether BSH or GB-10 was employed, the greatest enhancing effect was observed with TF-PEG liposomes followed in decreasing order by PEG liposomes, bare liposomes, and free BSH or GB-10 solution. In Q cells, the decrease was remarkable between PEG and bare liposomes. CONCLUSIONS: In terms of biodistribution characteristics and tumor cell-killing effect as a whole, including Q cells, GB-10 TF-PEG liposomes were regarded as promising (10)B-carriers.
Asunto(s)
Borohidruros/administración & dosificación , Compuestos de Boro/administración & dosificación , Terapia por Captura de Neutrón de Boro/métodos , Portadores de Fármacos/administración & dosificación , Compuestos de Sulfhidrilo/administración & dosificación , Animales , Borohidruros/farmacocinética , Bromodesoxiuridina , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Portadores de Fármacos/farmacocinética , Liposomas , Ratones , Pruebas de Micronúcleos , Polietilenglicoles , Compuestos de Sulfhidrilo/farmacocinética , TransferrinaRESUMEN
In order to improve the effectiveness of boron neutron capture therapy (BNCT) for malignant gliomas, we examined the optimization of the administration of boron compounds in brain tumor animal model. We analyzed the concentration of boron atoms in intracranial C6 glioma -bearing rats using inductively coupled plasma atomic emission spectrometry. Each tumor-bearing rat received one of two different amounts of sodium borocaptate (BSH) and/or 500 mg/kg of boronophenylalanine (BPA) via intraperitoneal injection. We compared the boron concentrations of the tumor, the contralateral normal brain and the blood in rats of 3 different treatment groups (BSH alone, BPA alone and a combination of both BSH and BPA). Our results show that the tumor boron concentration increased much more than 30 microg/g by the coadministration of both compounds. Additionally, the blood boron concentration remained below 30 microg/g and the boron concentration in the normal brain was low (mean 4.7+/-1.1 microg/g). Even in comparison with the administration of BPA alone, coadministration of BPA and BSH shows an improved tumor/normal brain ratio of boron concentrations.
Asunto(s)
Borohidruros/farmacocinética , Compuestos de Boro/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Fenilalanina/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Compuestos de Sulfhidrilo/farmacocinética , Animales , Borohidruros/administración & dosificación , Borohidruros/sangre , Compuestos de Boro/administración & dosificación , Compuestos de Boro/sangre , Encéfalo/metabolismo , Neoplasias Encefálicas/radioterapia , Combinación de Medicamentos , Sinergismo Farmacológico , Glioma/radioterapia , Masculino , Fenilalanina/administración & dosificación , Fenilalanina/sangre , Fenilalanina/farmacocinética , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Dosificación Radioterapéutica , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/sangreRESUMEN
Tumour cell destruction in boron neutron-capture therapy (BNCT) is due to the nuclear reaction between (10)B and thermal neutrons. It is necessary for effective BNCT therapy to accumulate (10)B atoms in the tumour cells. The delivery system consisted of polyethylene-glycol (PEG) binding liposomes (DPPC/cholesterol/DSPC-PEG2000) with an entrapped (10)B-compound and we evaluated the cytotoxic effects of intravenously injected (10)B-PEG-liposomes on human pancreatic carcinoma xenografts in nude mice with thermal neutron irradiation. After thermal neutron irradiation of mice injected with (10)B-PEG-liposomes, growth of AsPC-1 tumours was suppressed relative to controls. Injection of (10)B-PEG-liposomes caused the greatest tumour suppression with thermal neutron irradiation in vivo. These results suggest that intravenous injection of (10)B-PEG-liposomes can increase the retention of (10)B atoms by tumour cells, causing suppression of tumour growth in vivo, after thermal neutron irradiation.