Translational Radiobiological Boron Neutron Capture Therapy (BNCT) Studies for the Treatment of Different Pathologies: A Bench to Bedside Approach

Boron Neutron Capture Therapy (BNCT) is a binary cancer treatment modality that combines irradiation with a thermal or epithermal neutron beam with the administration of boron-10 carriers that are taken up preferentially by neoplastic cells. The high linear energy transfer alpha particles and recoiling 7 Li nuclei emitted during the boron-10 neutron-capture reaction 10B(n,α)7 Li, have a range of 5-9 µm in tissue and are known to have a high Relative Biological Effectiveness (RBE). In this way, BNCT would potentially target tumor tissue selectively, largely sparing normal tissue. Clinical trials of BNCT for the treatment of glioblastoma multiforme and/ or melanoma and, more recently, head and neck tumors, liver metastases, lung metastases and mesothelioma have been performed or are under way in Argentina, Europe, Japan, Taiwan, and the US. To date, the clinical results have shown a potential therapeutic advantage for this technique but undoubtedly leave room for improvement. Translational radiobiological studies in appropriate in vivo experimental models are pivotal to progress in this field. A significant part of our translational research efforts have been focused on exploring new applications of BNCT and optimizing BNCT for different pathologies, employing a bench to bedside approach that bridges the gap between research and clinical application. Although our work includes the assessment of the therapeutic potential of novel boron compounds in our experimental models, a large proportion of our studies have been devoted to optimize the delivery of boron compounds currently authorized for their use in humans such as Boron phenylalanine (BPA) and decahydrodecaborate (GB-10). In addition, we have designed and tested different BNCT treatment strategies tailored for different pathologies, for varying degrees of disease progression and for different clinical conditions of the patient. Some examples involve: 1) The combined use of BPA and GB-10 to improve tumor boron targeting homogeneity in the hamster cheek pouch oral cancer model, in a colon carcinoma liver metastases model in BDIX rats and in a diffuse lung metastases model in BDIX rats; 2) Aberrant tumor blood vessel normalization to improve boron delivery in the oral cancer model; 3) Sequential BNCT (BPA-BNCT followed by GB-10- BNCT with a 24-48 h interval) in the oral cancer model to optimize therapeutic efficacy and minimize mucositis in the dose-limiting precancerous tissue in the case of patients requiring abbreviated treatment; 4) Electroporation to improve the micro distribution of boron delivered by GB-10 in the oral cancer model; 5) Double applications of BNCT with 4-6 weeks interval to optimize therapeutic efficacy, reduce toxicity in terms of mucositis and inhibit the development of second primary tumors from precancerous tissue in the oral cancer model for the case of patients that do not require abbreviated treatment; 5) Assessment of the therapeutic efficacy and potential toxicity of BNCT in the liver metastases and diffuse lung metastases models in BDIX rats; 6) Local administration of GB10 or BPA for effective low dose Boron Neutron Capture Synovectomy (BNCS) for the treatment of Rheumatoid Arthritis in a model of antigen-induced arthritis in rabbits; 7) BNCT-induced local and abscopal effect in an ectopic model of colon carcinoma in BDIX rats. The knowledge gained from these radiobiological studies would contribute to design safe and effective clinical BNCT protocols. In particular, the BNCT protocols used to perform our ongoing and to date successful clinical-veterinary BNCT studies at RA-6 for cats and dogs with spontaneous head and neck cancer with no therapeutic option, are partially based on the lessons learnt from these translational studies.Fil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Teachings of our translational studies on boron neutron capture therapy (BNCT): thinking “outside the box”

BNCT is a technique for the treatment of solid tumors. BNCT is considered a binary technique because it involves two components that exert little or no action individually but induce a significant effect when they combine. BNCT is based on the combination of neutron irradiation and the administration of 10B compounds that are incorporated selectively by tumor tissue via different mechanisms, depending on the boron carrier.Fil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Palmieri, Mónica Alejandra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Optimization of the classical oral cancerization protocol in hamster to study oral cancer therapy

Objective(s): The hamster carcinogenesis model recapitulates oral oncogenesis. Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. “Short” pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. Materials and methods: We studied: Classical cancerization protocol (24 applications) and Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. Results: The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis versus the non-interrupted group (17% versus 71%) and a significantly higher incidence of long pouches (100% versus 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. Conclusion(s): The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.Objective(s): The hamster carcinogenesis model recapitulates oral oncogenesis. Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. “Short” pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. Materials and methods: We studied: Classical cancerization protocol (24 applications) and Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. Results: The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis versus the non-interrupted group (17% versus 71%) and a significantly higher incidence of long pouches (100% versus 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. Conclusion(s): The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.Fil: Santa Cruz, Iara Sofía. Comisión Nacional de Energía Atómica; ArgentinaFil: Santa Cruz, Iara Sofía. Comisión Nacional de Energía Atómica; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica; ArgentinaFil: Trivillin, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Trivillin, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Itoiz, María Elina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Itoiz, María Elina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Guidobono, Juan Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; ArgentinaFil: Guidobono, Juan Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Schwint, Amanda Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Schwint, Amanda Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Monti Hughes, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Monti Hughes, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentin

Boron Neutron Capture Therapy (BNCT) in an oral precancer model: Therapeutic benefits and potential toxicity of a double application of BNCT with a six-week interval

Given the clinical relevance of locoregional recurrences in head and neck cancer, we developed a novel experimental model of premalignant tissue in the hamster cheek pouch for long-term studies and demonstrated the partial inhibitory effect of a single application of Boron Neutron Capture Therapy (BNCT) on tumor development from premalignant tissue. The aim of the present study was to evaluate the effect of a double application of BNCT with a 6 week interval in terms of inhibitory effect on tumor development, toxicity and DNA synthesis. We performed a double application, 6 weeks apart, of (1) BNCT mediated by boronophenylalanine (BPA-BNCT); (2) BNCT mediated by the combined application of decahydrodecaborate (GB-10) and BPA [(GB-10 + BPA)-BNCT] or (3) beam-only, at RA-3 nuclear reactor and followed the animals for 8 months. The control group was cancerized and sham-irradiated. BPA-BNCT, (GB-10 + BPA)-BNCT and beam-only induced a reduction in tumor development from premalignant tissue that persisted until 8, 3, and 2 months respectively. An early maximum inhibition of 100% was observed for all 3 protocols. No normal tissue radiotoxicity was detected. Reversible mucositis was observed in premalignant tissue, peaking at 1 week and resolving by the third week after each irradiation. Mucositis after the second application was not exacerbated by the first application. DNA synthesis was significantly reduced in premalignant tissue 8 months post-BNCT. A double application of BPA-BNCT and (GB-10 + BPA)-BNCT, 6 weeks apart, could be used therapeutically at no additional cost in terms of radiotoxicity in normal and dose-limiting tissues.Fil: Monti Hughes, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Comision Nacional de Energia Atomica. Gerencia D/area de Energia Nuclear. Gerencia de Ingenieria Nuclear (cab). Departamento de Reactores de Investigacion.; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Thorp, Silvia Inés. Comision Nacional de Energia Atomica. Gerencia de Area Carem. Departamento de Instrumentacion y Cableado (cab).; ArgentinaFil: Miller, Marcelo. Comision Nacional de Energia Atomica. Gerencia de Area Carem. Departamento de Instrumentacion y Cableado (cab).; ArgentinaFil: Itoiz, María Elina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Aromando, Romina F.. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Molinari, Ana Julia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Trivillin, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Schwint, Amanda Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentin

Extending neutron autoradiography technique for boron concentration measurements in hard tissues

The neutron autoradiography technique using polycarbonate nuclear track detectors (NTD) has been extended to quantify the boron concentration in hard tissues, an application of special interest in Boron Neutron Capture Therapy (BNCT). Chemical and mechanical processing methods to prepare thin tissue sections as required by this technique have been explored. Four different decalcification methods governed by slow and fast kinetics were tested in boron-loaded bones. Due to the significant loss of the boron content, this technique was discarded. On the contrary, mechanical manipulation to obtain bone powder and tissue sections of tens of microns thick proved reproducible and suitable, ensuring a proper conservation of the boron content in the samples. A calibration curve that relates the 10B concentration of a bone sample and the track density in a Lexan NTD is presented. Bone powder embedded in boric acid solution with known boron concentrations between 0 and 100 ppm was used as a standard material. The samples, contained in slim Lexan cases, were exposed to a neutron fluence of 1012 cm−2 at the thermal column central facility of the RA-3 reactor (Argentina). The revealed tracks in the NTD were counted with an image processing software. The effect of track overlapping was studied and corresponding corrections were implemented in the presented calibration curve. Stochastic simulations of the track densities produced by the products of the 10B thermal neutron capture reaction for different boron concentrations in bone were performed and compared with the experimental results. The remarkable agreement between the two curves suggested the suitability of the obtained experimental calibration curve. This neutron autoradiography technique was finally applied to determine the boron concentration in pulverized and compact bone samples coming from a sheep experimental model. The obtained results for both type of samples agreed with boron measurements carried out by ICP-OES within experimental uncertainties. The fact that the histological structure of bone sections remains preserved allows for future boron microdistribution analysis.Fil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Olivera, María Silvina. Comisión Nacional de Energía Atómica; ArgentinaFil: Saint Martin, María Laura Gisela. Comisión Nacional de Energía Atómica; ArgentinaFil: Rodriguez, Luis Miguel. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Fregenal, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Postuma, Ian. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Altieri, Saverio. Istituto Nazionale di Fisica Nucleare; Italia. Universita Degli Studi Di Pavia; ItaliaFil: González, Sara Josefina. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bortolussi, Silva. Istituto Nazionale di Fisica Nucleare; Italia. Universita Degli Studi Di Pavia; ItaliaFil: Portu, Agustina Mariana. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Tumor blood vessel ''normalization'' improves the therapeutic efficacy of boron neutron capture therapy (BNCT) in experimental oral cancer

We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer. Blood vessel normalization was induced by two doses of thalidomide in tumor-bearing hamsters on 2 consecutive days. All studies in thalidomide-treated animals were performed 48 h after the first dose of thalidomide, previously established as the window of normalization. Biodistribution studies were performed with BPA at a dose of 15.5 mg 10B/kg in thalidomide-treated (Th+) and untreated (Th–) tumorbearing hamsters. The effect of blood vessel normalization prior to BPA administration on the efficacy of BNCT was assessed in in vivo BNCT studies at the RA-3 Nuclear Reactor in tumor-bearing hamsters. Group I was treated with BPABNCT after treatment with thalidomide (Th+ BPA-BNCT). Group II was treated with BPA-BNCT alone (Th– BPABNCT). Group III was treated with the beam only after treatment with thalidomide (Th+ BO), and Group IV was treated with the beam only (Th– BO). Groups I and II were given the same dose of BPA (15.5 mg 10B/kg), and all groups (I–IV) were exposed to the same neutron fluence. Two additional groups were treated with the beam only at a higher dose to exacerbate mucositis in precancerous tissue and to explore the potential direct protective effect of thalidomide on radiation-induced mucositis in a scenario of more severe toxicity, i.e. Group V (Th+ hdBO) and Group VI (Th– hdBO). The animals were followed for 28 days. Biodistribution studies revealed no statistically significant differences in gross boron content between Th+ and Th– animals. Overall tumor control (complete response + partial response) at 28 days post-treatment was significantly higher for Group I (Th+ BPA-BNCT) than for Group II (Th– BPA-BNCT): 84 6 3% compared to 67 6 5%. Pretreatment with thalidomide did not induce statistically significant changes in overall tumor control induced by the beam only, i.e. 15 6 5% in Group III (Th+ BO) and 18 6 5% in Group IV (Th– BO), or in overall tumor control induced by the high-dose beam only, i.e. 60 6 7% in Group V (Th+ hdBO) and 47 6 10% in Group VI (Th– hdBO). BPA-BNCT alone (Group II) induced mucositis in precancerous tissue that reached Grades 3–4 in 80% of the animals, whereas pretreatment with thalidomide (Group I) prevented mucositis Grades 3 and 4 completely. Beam-only Group III (Th+ BO) exhibited only Grade 1 mucositis in precancerous tissue, whereas 17% of the animals in beamonly Group IV (Th– BO) reached Grade 2 mucositis. Highdose beam-only group V (Th+ hdBO) exhibited only Grade 2 mucositis, whereas high-dose beam-only group VI (Th– hdBO) reached Grade 3 mucositis in 83% of the animals. In all cases mucositis in precancerous tissue was reversible. No normal tissue radiotoxicity was observed with any of the protocols. Pretreatment with thalidomide enhanced the therapeutic efficacy of BNCT and reduced precancerous tissue toxicity.Fil: Molinari, Ana Julia. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Ezeiza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica. Centro Atómico Ezeiza; ArgentinaFil: Miller, Marcelo Eduardo. Comisión Nacional de Energía Atómica. Centro Atómico Ezeiza; ArgentinaFil: Itoiz, María Elina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aromando, Romina Flavia. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

The application of boron neutron capture therapy (BNCT) mediated by liposomes containing 10B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the hamster cheek pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH3(CH2)15-7,8-C2B9H11] (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na3[ae-B20H17NH3] (TAC) in the aqueous core. Unilamellar liposomes with a mean diameter of 83 nm were administered i.v. in hamsters. After 48 h, the boron concentration in tumors was 67 ± 16 ppm whereas the precancerous tissue contained 11 ± 6 ppm, and the tumor/normal pouch tissue boron concentration ratio was 10:1. Neutron irradiation giving a 5-Gy dose to precancerous tissue (corresponding to 21 Gy in tumor) resulted in an overall tumor response (OR) of 70% after a 4-wk posttreatment period. In contrast, the beam-only protocol gave an OR rate of only 28%. Once-repeated BNCT treatment with readministration of liposomes at an interval of 4, 6, or 8 wk resulted in OR rates of 70–88%, of which the complete response ranged from 37% to 52%. Because of the good therapeutic outcome, it was possible to extend the follow-up of BNCT treatment groups to 16 wk after the first treatment. No radiotoxicity to normal tissue was observed. A salient advantage of these liposomes was that only mild mucositis was observed in dose-limiting precancerous tissue with a sustained tumor response of 70–88%.Fil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Hawthorne, M. Frederick. University of Missouri; Estados UnidosFil: Kueffer, Peter J.. University of Missouri; Estados UnidosFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Maitz, Charles A.. University of Missouri; Estados UnidosFil: Jalisatgi, Satish S.. University of Missouri; Estados UnidosFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

A Small-Animal Irradiation Facility for Neutron Capture Therapy Research at the RA-3 Research Reactor

The National Atomic Energy Commission of Argentina (CNEA) has constructed a thermal neutron source for use in Boron Neutron Capture Therapy (BNCT) applications at the RA-3 research reactor facility located in Buenos Aires. The Idaho National Laboratory (INL) and CNEA have jointly conducted some initial neutronic characterization measurements for one particular configuration of this source. The RA-3 reactor (Figure 1) is an open pool type reactor, with 20% enriched uranium plate-type fuel and light water coolant. A graphite thermal column is situated on one side of the reactor as shown. A tunnel penetrating the graphite structure enables the insertion of samples while the reactor is in normal operation. Samples up to 14 cm height and 15 cm width are accommodated

"Sequential" boron neutron capture therapy (BNCT): A novel approach to BNCT for the treatment of oral cancer in the hamster cheek pouch model

In the present study the therapeutic effect and potential toxicity of the novel "“Sequential"†boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential"BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential"BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ±2% and 91 ±3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ±5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 ±12% and 60 ±22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential"BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue.Fil: Molinari, Ana Julia. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Miller, Marcelo. Comisión Nacional de Energía Atómica; ArgentinaFil: Itoiz, María Elina. Universidad de Buenos Aires; Argentina. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aromando, Romina F.. Universidad de Buenos Aires; ArgentinaFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Quintana, Jorge. Comisión Nacional de Energía Atómica; ArgentinaFil: Santa Cruz, Gustavo Alberto. Comisión Nacional de Energía Atómica; ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Experimental set up for the irradiation of biological samples and nuclear track detectors with UV C

AimIn this work we present a methodology to produce an “imprint” of cells cultivated on a polycarbonate detector by exposure of the detector to UV C radiation.BackgroundThe distribution and concentration of 10B atoms in tissue samples coming from BNCT (Boron Neutron Capture Therapy) protocols can be determined through the quantification and analysis of the tracks forming its autoradiography image on a nuclear track detector. The location of boron atoms in the cell structure could be known more accurately by the simultaneous observation of the nuclear tracks and the sample image on the detector.Materials and MethodsA UV C irradiator was constructed. The irradiance was measured along the lamp direction and at different distances. Melanoma cells were cultured on polycarbonate foils, incubated with borophenylalanine, irradiated with thermal neutrons and exposed to UV C radiation. The samples were chemically attacked with a KOH solution.ResultsA uniform irradiation field was established to expose the detector foils to UV C light. Cells could be seeded on the polycarbonate surface. Both imprints from cells and nuclear tracks were obtained after chemical etching.ConclusionsIt is possible to yield cellular imprints in polycarbonate. The nuclear tracks were mostly present inside the cells, indicating a preferential boron uptake