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Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy. It combines preferential boron accumulation in tumors and neutron irradiation. The recent initiation of BNCT clinical trials employing hospital-based accelerators rather than nuclear reactors as the neutron source will conceivably pave the way for new and more numerous clinical trials, leading up to much-needed randomized trials. In this context, it would be interesting to consider the implementation of new boron compounds and strategies that will significantly optimize BNCT. With this aim in mind, we analyzed, in this review, those articles published between 2020 and 2023 reporting new boron compounds and strategies that were proved therapeutically useful in in vitro and/or in vivo radiobiological studies, a critical step for translation to a clinical setting. We also explored new pathologies that could potentially be treated with BNCT and newly developed theranostic boron agents. All these radiobiological advances intend to solve those limitations and questions that arise during patient treatment in the clinical field, with BNCT and other therapies. In this sense, active communication between clinicians, radiobiologists, and all disciplines will improve BNCT for cancer patients, in a cost- and time-effective way.

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Boron neutron capture therapy (BNCT) is based on the preferential uptake of 10B compounds by tumors, followed by neutron irradiation. The aim of this study was to assess, in an ectopic colon cancer model, the therapeutic efficacy, radiotoxicity, abscopal effect and systemic immune response associated with (BPA/Borophenylalanine+GB-10/Decahydrodecaborate)-BNCT (Comb-BNCT) alone or in combination with Oligo-Fucoidan (O-Fuco) or Glutamine (GLN), compared to the "standard" BPA-BNCT protocol usually employed in clinical trials. All treatments were carried out at the RA-3 nuclear reactor. Boron biodistribution studies showed therapeutic values above 20 ppm 10B in tumors. At 7 weeks post-treatment, the ratio of tumor volume post-/pre-BNCT was significantly smaller for all BNCT groups vs. SHAM (p < 0.05). The parameter "incidence of tumors that underwent a reduction to ≤50% of initial tumor volume" exhibited values of 62% for Comb-BNCT alone, 82% for Comb-BNCT+GLN, 73% for Comb-BNCT+O-Fuco and only 30% for BPA-BNCT. For BPA-BNCT, the incidence of severe dermatitis was 100%, whereas it was significantly below 70% (p ≤ 0.05) for Comb-BNCT, Comb-BNCT+O-Fuco and Comb-BNCT+GLN. Considering tumors outside the treatment area, 77% of Comb-BNCT animals had a tumor volume lower than 50 mm3 vs. 30% for SHAM (p ≤ 0.005), suggesting an abscopal effect of Comb-BNCT. Inhibition of metastatic spread to lymph nodes was observed in all Comb-BNCT groups. Considering systemic aspects, CD8+ was elevated for Comb-BNCT+GLN vs. SHAM (p ≤ 0.01), and NK was elevated for Comb-BNCT vs. SHAM (p ≤ 0.05). Comb-BNCT improved therapeutic efficacy and reduced radiotoxicity compared to BPA-BNCT and induced an immune response and an abscopal effect.

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The assessment of boron microdistribution is essential to evaluate the suitability of boron neutron capture therapy (BNCT) in different biological models. In our laboratory, we have reported a methodology to produce cell imprints on polycarbonate through UV-C sensitization. The aim of this work is to extend the technique to tissue samples in order to enhance spatial resolution. As tissue structure largely differs from cultured cells, several aspects must be considered. We studied the influence of the parameters involved in the imprint and nuclear track formation, such as neutron fluence, different NTDs, etching and UV-C exposure times, tissue absorbance, thickness, and staining, among others. Samples from different biological models of interest for BNCT were used, exhibiting homogeneous and heterogeneous histology and boron microdistribution. The optimal conditions will depend on the animal model under study and the resolution requirements. Both the imprint sharpness and the fading effect depend on tissue thickness. While 6 h of UV-C was necessary to yield an imprint in CR-39, only 5 min was enough to observe clear imprints on Lexan. The information related to microdistribution of boron obtained with neutron autoradiography is of great relevance when assessing new boron compounds and administration protocols and also contributes to the study of the radiobiology of BNCT.

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Boron neutron capture therapy (BNCT) combines preferential tumor uptake of 10B compounds and neutron irradiation. Electroporation induces an increase in the permeability of the cell membrane. We previously demonstrated the optimization of boron biodistribution and microdistribution employing electroporation (EP) and decahydrodecaborate (GB-10) as the boron carrier in a hamster cheek pouch oral cancer model. The aim of the present study was to evaluate if EP could improve tumor control without enhancing the radiotoxicity of BNCT in vivo mediated by GB-10 with EP 10 min after GB-10 administration. Following cancerization, tumor-bearing hamster cheek pouches were treated with GB-10/BNCT or GB-10/BNCT + EP. Irradiations were carried out at the RA-3 Reactor. The tumor response and degree of mucositis in precancerous tissue surrounding tumors were evaluated for one month post-BNCT. The overall tumor response (partial remission (PR) + complete remission (CR)) increased significantly for protocol GB-10/BNCT + EP (92%) vs. GB-10/BNCT (48%). A statistically significant increase in the CR was observed for protocol GB-10/BNCT + EP (46%) vs. GB-10/BNCT (6%). For both protocols, the radiotoxicity (mucositis) was reversible and slight/moderate. Based on these results, we concluded that electroporation improved the therapeutic efficacy of GB-10/BNCT in vivo in the hamster cheek pouch oral cancer model without increasing the radiotoxicity.

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Boron neutron capture therapy (BNCT) is a cancer treatment option that combines preferential uptake of a boron compound in tumors and irradiation with thermal neutrons. For treatment planning, the boron concentration in different tissues must be considered. Neutron autoradiography using nuclear track detectors (NTD) can be applied to study both the concentration and microdistribution of boron in tissue samples. Histological sections are obtained from frozen tissue by cryosectioning. When the samples reach room temperature, they undergo an evaporation process, which leads to an increase in the boron concentration. To take this effect into account, certain correction factors (evaporation coefficients, CEv) must be applied. With this aim, a protocol was established to register and analyze mass variation of tissue sections, measured with a semimicro scale. Values of ambient temperature, pressure, and humidity were simultaneously recorded. Reproducible results of evaporation curves and CEv values were obtained for different tissue samples, which allowed the systematization of the procedure. This study could contribute to a more precise determination of boron concentration in tissue samples through the neutron autoradiography technique, which is of great relevance to make dosimetric calculations in BNCT.

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Translational research in adequate experimental models is necessary to optimize boron neutron capture therapy (BNCT) for different pathologies. Multiple radiobiological in vivo studies have been performed in a wide variety of animal models, studying multiple boron compounds, routes of compound administration, and a range of administration strategies. Animal models are useful for the study of the stability and potential toxicity of new boron compounds or delivery systems, BNCT theranostic strategies, the evaluation of biomarkers to monitor BNCT therapeutic and adverse effects, and to study the BNCT immune response by the host against tumor cells. This article will mention examples of these studies, highlighting the importance of experimental animal models for the advancement of BNCT. Animal models are essential to design novel, safe, and effective clinical BNCT protocols for existing or new targets for BNCT.

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BACKGROUND: BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Although p-boronophenylalanine (BPA) has been clinically used, new boron compounds are needed for the advancement of BNCT. Based on previous studies in colon tumor-bearing mice, in this study, we evaluated MID:BSA (maleimide-functionalized closo-dodecaborate conjugated to bovine serum albumin) biodistribution and MID:BSA/BNCT therapeutic effect on tumors and associated radiotoxicity in the hamster cheek pouch oral cancer model. METHODS: Biodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue. RESULTS: MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity. CONCLUSIONS: MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied.

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Boron neutron capture therapy (BNCT) is a tumour selective particle radiotherapy, based on the administration of boron carriers incorporated preferentially by tumour cells, followed by irradiation with a thermal or epithermal neutron beam. BNCT clinical results to date show therapeutic efficacy, associated with an improvement in patient quality of life and prolonged survival. Translational research in adequate experimental models is necessary to optimise BNCT for different pathologies. This review recapitulates some examples of BNCT radiobiological studies for different pathologies and clinical scenarios, strategies to optimise boron targeting, enhance BNCT therapeutic effect and minimise radiotoxicity. It also describes the radiobiological mechanisms induced by BNCT, and the importance of the detection of biomarkers to monitor and predict the therapeutic efficacy and toxicity of BNCT alone or combined with other strategies. Besides, there is a brief comment on the introduction of accelerator-based neutron sources in BNCT. These sources would expand the clinical BNCT services to more patients, and would help to make BNCT a standard treatment modality for various types of cancer. Radiobiological BNCT studies have been of utmost importance to make progress in BNCT, being essential to design novel, safe and effective clinical BNCT protocols.

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PURPOSE: A new type of electronic dosimeter is presented, capable of discerning between the doses of gamma photons and neutrons in a mixed beam as found in boron neutron capture therapy (BNCT). We introduce a real-time dosimeter based on a thick gate field oxide field effect transistor (FOXFET) covered with a neutron converter layer containing gadolinium. METHODS: To sensitize the FOXFET dosimeter to neutron fluxes, a converter layer containing gadolinium oxide particles embedded in photoresines was deposited over the sensor surface. Mixed neutron-gamma field configurations with different neutron energy spectra were used to assess the FOXFET response, considering different thicknesses of the neutron converter layer. RESULTS: The total gamma sensitivity of the devices resulted to be 43 mV/Gy. The responses of sensors with different converter layer thicknesses irradiated with different neutron spectra are simulated using GEANT4 code. The response to photons is not significantly modified with thin conversion layers when used in water medium. CONCLUSIONS: A real-time dosimeter comprising a pair of FOXFET sensors-only one of them with a gadolinium neutron converter layer-allows the simultaneous measurement of gamma dose and neutron flux during BNCT irradiations.

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Translational Boron Neutron Capture Therapy (BNCT) studies performed by our group and clinical BNCT studies worldwide have shown the therapeutic efficacy of BNCT for head and neck cancer. The present BNCT studies in veterinary patients with head and neck cancer were performed to optimize the therapeutic efficacy of BNCT, contribute towards exploring the role of BNCT in veterinary medicine, put in place technical aspects for an upcoming clinical trial of BNCT for head and neck cancer at the RA-6 Nuclear Reactor, and assess the feasibility of employing the existing B2 beam to treat large, deep-seated tumors. Five dogs with head and neck cancer with no other therapeutic option were treated with two applications of BNCT mediated by boronophenyl-alanine (BPA) separated by 3-5 weeks. Two to three portals per BNCT application were used to achieve a potentially therapeutic dose over the tumor without exceeding normal tissue tolerance. Clinical and Computed Tomography results evidenced partial tumor control in all cases, with slight-moderate mucositis, excellent life quality, and prolongation in the survival time estimated at recruitment. These exploratory studies show the potential value of BNCT in veterinary medicine and contribute towards initiating a clinical BNCT trial for head and neck cancer at the RA-6 clinical facility.

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Existing and active low-energy Accelerator-Based BNCT programs worldwide will be reviewed and compared. In particular, the program in Argentina will be discussed which consists of the development of an Electro-Static-Quadrupole (ESQ) Accelerator-Based treatment facility. The facility is conceived to operate with the deuteron-induced reactions 9Be(d,n)10B and 13C(d,n)14N at 1.45 MeV deuteron energy, as neutron sources. Neutron production target development status is specified. The present status of the construction of the new accelerator development laboratory and future BNCT centre is shown.

RESUMO

PURPOSE: The present study analyzed different protocols of administration of boronophenylalanine (BPA) and sodium butyrate (NaB) to increase the BNCT efficacy for poorly differentiated thyroid cancer (PDTC). MATERIALS AND METHODS: Nude mice implanted with human PDTC cells (WRO) were distributed into four protocols: 1) BPA; 2) BPA + ip NaB; 3) BPA + oral NaB; 4) Control. Biodistribution and histologic studies were performed. LAT (BPA transporter) isoforms gene expression was assessed by RT-PCR. RESULTS: Tumor growth delay was observed in animals of the Protocol #3 (p < 0.05). NaB (Protocol #2) increased tumor boron uptake 2-h post BPA injection (p < 0.05). On the other hand, NaB upregulated the expression of all the isoforms of the LAT transporter in vitro. Histologic studies showed a significant decrease of mitotic activity and an increase of vacuoles in tumors of Protocol #3. Neutrons alone or combined with NaB caused some tumor growth delay (p < 0.05), while in the BNCT and BNCT + NaB groups, there was a halt in tumor growth in 70 and 80% of the animals, respectively. CONCLUSIONS: Intraperitoneally administration of NaB increased boron uptake while oral administration for a longer period of time induced tumor growth delay previous to BPA administration. The use of NaB via ip would optimize the irradiation results.

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In Argentina, a multi-institutional project has been established to assess the feasibility of applying BNCT ex-situ to the treatment of patients with multiple metastases in both lungs. Within this context, this work aims at applying the neutron autoradiography technique to study boron microdistribution in the lung. A comprehensive analysis of the different aspects for the generation of autoradiographic images of both normal and metastatic BDIX rat lungs was achieved. Histology, boron uniformity, optimal tissue thickness and water content in tissue were explored for the two types of samples. A qualitative and a quantitative analysis were performed. No heterogeneities in uptake were observed in normal lung. Conversely, samples with metastasis showed preferential boron uptake in the tumour areas with respect to surrounding tissue. Surrounding tissue would present a slightly higher uptake of boron than the normal lung. Quantitative results of boron concentration values and ratios determined by neutron autoradiography were obtained. In order to contribute to BNCT dosimetry, further analysis increasing the number of samples is warranted.

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One of the driving forces of carcinogenesis in humans is the aberrant activation of receptors; consequently, one of the most promising mechanisms for cancer treatment is receptor inhibition by chemotherapy. Although a variety of cancers are initially susceptible to chemotherapy, they eventually develop multi-drug resistance. Anti-tumor agents overcoming resistance and acting through two or more ways offer greater therapeutic benefits over single-mechanism entities. In this study, we report on a new family of bifunctional compounds that, offering the possibility of dual action (drug + radiotherapy combinations), may result in significant clinical benefits. This new family of compounds combines two fragments: the drug fragment is a lapatinib group, which inhibits the tyrosine kinase receptor activity, and an icosahedral boron cluster used as agents for neutron capture therapy (BNCT). The developed compounds were evaluated in vitro against different tyrosine kinase receptors (TKRs)-expressing tumoral cells, and in vitro-BNCT experiments were performed for two of the most promising hybrids, 19 and 22. We identified hybrid 19 with excellent selectivity to inhibit cell proliferation and ability to induce necrosis/apoptosis of glioblastoma U87 MG cell line. Furthermore, derivative 22, bearing a water-solubility-enhancing moiety, showed moderate inhibition of cell proliferation in both U87 MG and colorectal HT-29 cell lines. Additionally, the HT-29 cells accumulated adequate levels of boron after hybrids 19 and 22 incubations rendering, and after neutron irradiation, higher BNCT-effects than BPA. The attractive profile of developed hybrids makes them interesting agents for combined therapy.

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PURPOSE: Boron Neutron Capture Therapy (BNCT) is a treatment modality that uses an external neutron beam to selectively inactive boron10-loaded tumor cells. This work presents the development and innovative use of radiobiological probability models to adequately evaluate and compare the therapeutic potential and versatility of beams presenting different neutron energy spectra. M&M: Aforementioned characteristics, collectively refer to as the performance of a beam, were defined on the basis of radiobiological probability models for the first time in BNCT. A model of uncomplicated tumor control probability (UTCP) for HN cancer was introduced. This model considers a NTCP able to predict severe mucositis and a TCP for non-uniform doses derived herein. A systematic study comprising a simplified HN cancer model is presented as a practical application of the introduced radiobiological figures of merit (FOM) for assessing and comparing the performance of different clinical beams. Applications involving treated HN cancer patients were also analyzed. RESULTS: The maximum UTCP proved suitable and sensitive to assess the performance of a beam, revealing particularities of the studied sources that the physical FOMs do not highlight. The radiobiological FOMs evaluated in patients showed to be useful tools both for retrospective analysis of the BNCT treatments, and for prospective studies of beam optimization and feasibility. CONCLUSIONS: The presented developments and applications demonstrated that it is possible to assess and compare performances of completely different beams fairly and adequately by assessing the radiobiological FOM UTCP. Thus, this figure would be a practical and essential aid to guide treatment decisions.

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Our group has reported the imprint formation of biological material on polycarbonate nuclear track detectors by UV-C exposure, which is used as an approach to simultaneously visualize cell imprints and nuclear tracks coming from the boron neutron capture reaction. Considering that the cell nucleus has a higher UV-C absorption than the cytoplasm and that hematoxylin preferentially stains the nucleus, we proposed to enhance the contrast between these two main cell structures by hematoxylin staining before UV-C sensitization. In this study, several experiments were performed in order to optimize UV-C exposure parameters and chemical etching conditions for cell imprint formation using the SK-BR-3 breast cancer cell line. The proposed method improves significantly the resolution of the cell imprints. It allows clear differentiation of the nucleus from the rest of the cell, together with nuclear tracks pits. Moreover, it reduces considerably the UV-C exposure time, an important experimental issue. The proposed methodology can be applied to study the boron distribution independently from the chosen cell line and/or boron compounds.

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Boron neutron capture therapy (BNCT) is a targeted therapy, which consists of preferential accumulation of boron carriers in tumor followed by neutron irradiation. Each oral cancer patient has different risks of developing one or more carcinomas and/or oral mucositis induced after treatment. Our group proposed the hamster oral cancer model to study the efficacy of BNCT and associated mucositis. Translational studies are essential to the advancement of novel boron delivery agents and targeted strategies. Herein, we review our work in the hamster model in which we studied BNCT induced mucositis using three different cancerization protocols, mimicking three different clinical scenarios. The BNCT-induced mucositis increases with the aggressiveness of the carcinogenesis protocol employed, suggesting that the study of different oral cancer patient scenarios would help to develop personalized therapies.

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Boron neutron capture therapy (BNCT) is a promising cancer binary therapy modality that utilizes the nuclear capture reaction of thermal neutrons by boron-10 resulting in a localized release of high- and low-linear energy transfer (LET) radiation. Electrochemotherapy (ECT) is based on electroporation (EP) that induces opening of pores in cell membranes, allowing the entry of compounds. Because EP is applied locally to a tumor, the compound is incorporated preferentially by tumor cells. Based on the knowledge that the therapeutic success of BNCT depends centrally on the boron content in tumor and normal tissues and that EP has proven to be an excellent facilitator of tumor biodistribution of an anti-tumor agent, the aim of this study was to evaluate if EP can optimize the delivery of boronated compounds. We performed biodistribution studies and qualitative microdistribution analyses of boron employing the boron compound sodium decahydrodecaborate (GB-10) + EP in the hamster cheek pouch oral cancer model. Syrian hamsters with chemically induced exophytic squamous cell carcinomas were used. A typical EP treatment was applied to each tumor, varying the moment of application with respect to the administration of GB-10 (early or late). The results of this study showed a significant increase in the absolute and relative tumor boron concentration and optimization of the qualitative microdistribution of boron by the use of early EP + GB-10 versus GB-10 without EP. This strategy could be a tool to improve the therapeutic efficacy of BNCT/GB-10 in vivo.

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PURPOSE: Boron neutron capture therapy (BNCT) combines selective accumulation of 10B carriers in tumor tissue with subsequent neutron irradiation. BNCT has been proposed for the treatment of multiple, non-resectable, diffuse tumors in lung. The aim of the present study was to evaluate the therapeutic efficacy and toxicity of BNCT in an experimental model of lung metastases of colon carcinoma in BDIX rats and perform complementary survival studies. MATERIALS AND METHODS: We evaluated tumor control and toxicity in lung 2 weeks post-BNCT at 2 dose levels, including 5 experimental groups per dose level: T0 (euthanized pre-treatment), Boronophenylalanine-BNCT (BPA-BNCT), BPA + Sodium decahydrodecaborate-BNCT ((BPA + GB-10)-BNCT), Beam only (BO) and Sham (no treatment, same manipulation). Tumor response was assessed employing macroscopic and microscopic end-points. An additional experiment was performed to evaluate survival and oxygen saturation in blood. RESULTS AND CONCLUSIONS: No dose-limiting signs of short/medium-term toxicity were observed in lung. All end-points revealed statistically significant BNCT-induced tumor control vs Sham at both dose levels. The survival experiment showed a statistically significant 45% increase in post-treatment survival time in the BNCT group (48 days) versus Sham (33 days). These data consistently revealed growth suppression of lung metastases by BNCT with no manifest lung toxicity. Highlights Boron Neutron Capture Therapy suppresses growth of experimental lung metastases No BNCT-induced short/medium-term toxicity in lung is associated with tumor control Boron Neutron Capture Therapy increased post-treatment survival time by 45.

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The analysis of the distribution and density of nuclear tracks forming an autoradiography in a nuclear track detector (NTD) allows the determination of 10B atoms concentration and location in tissue samples from Boron Neutron Capture Therapy (BNCT) protocols. This knowledge is of great importance for BNCT dosimetry and treatment planning. Tissue sections studied with this technique are obtained by cryosectioning frozen tissue specimens. After the slicing procedure, the tissue section is put on the NTD and the sample starts drying. The thickness varies from its original value allowing more particles to reach the detector and, as the mass of the sample decreases, the boron concentration in the sample increases. So in order to determine the concentration present in the hydrated tissue, the application of corrective coefficients is required. Evaporation mechanisms as well as various factors that could affect the process of mass variation are outlined in this work. Mass evolution for tissue samples coming from BDIX rats was registered with a semimicro analytical scale and measurements were analyzed with software developed to that end. Ambient conditions were simultaneously recorded, obtaining reproducible evaporation curves. Mathematical models found in the literature were applied for the first time to this type of samples and the best fit of the experimental data was determined. The correlation coefficients and the variability of the parameters were evaluated, pointing to Page's model as the one that best represented the evaporation curves. These studies will contribute to a more precise assessment of boron concentration in tissue samples by the Neutron Autoradiography technique.

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