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Simple Summary: Many boron-containing compounds have been synthesized and proposed as boron-delivery agents for boron neutron capture therapy for cancers, including brain tumors and melanomas. However, only a few have been investigated in clinical studies, leaving their potential efficacy for cancer treatment unknown. With the recent availability of accelerator-based neutron sources, clinical trials are underway using the boronated amino acid (L)-4-hydroxyboryl phenylalanine. Simultaneously, there is renewed interest in the development of multi-functional boron-delivery agents for cancer diagnosis and treatment. Promising agents can deliver therapeutic amounts of boron into tumor cells with high specificity and low toxicity. Among the different classes of boron-containing compounds, peptide-, porphyrin-, liposome-, and nanoparticle-based-delivery agents are the most promising due to their tumor-targeting and concurrent imaging abilities. A systematic and comparative evaluation of these agents in clinical trials would allow the determination of their full potential for cancer treatment. Boron neutron capture therapy (BNCT) is a binary cancer treatment that involves the irradiation of 10B-containing tumors with low-energy neutrons (thermal or epithermal). The alpha particles and recoiling Li nuclei that are produced in the 10B-capture nuclear reaction are high-linear-energy transfer particles that destroy boron-loaded tumor cells; therefore, BNCT has the potential to be a localized therapeutic modality. Two boron-delivery agents have been used in clinical trials of BNCT in patients with malignant brain tumors, cutaneous melanoma, or recurrent tumors of the head and neck region, demonstrating the potential of BNCT in the treatment of difficult cancers. A variety of potentially highly effective boron-delivery agents have been synthesized in the past four decades and tested in cells and animal models. These include boron-containing nucleosides, peptides, proteins, polyamines, porphyrins, liposomes, monoclonal antibodies, and nanoparticles of various types. The most promising agents are multi-functional boronated molecules and nanoparticles functionalized with tumor cell-targeting moieties that increase their tumor selectivity and contain a radiolabel or fluorophore to allow quantification of 10B-biodistribution and treatment planning. This review discusses multi-functional boron agents reported in the last decade, but their full potential can only be ascertained after their evaluation in BNCT clinical trials. [ABSTRACT FROM AUTHOR]

This proceeding article compiles current research on the development of boron delivery drugs for boron neutron capture therapy that was presented and discussed at the National Cancer Institute (NCI) Workshop on Neutron Capture Therapy that took place on April 20-22, 2022. The most used boron sources are icosahedral boron clusters attached to peptides, proteins (such as albumin), porphyrin derivatives, dendrimers, polymers, and nanoparticles, or encapsulated into liposomes. These boron clusters and/or carriers can be labeled with contrast agents allowing for the use of imaging techniques, such as PET, SPECT, and fluorescence, that enable quantification of tumor-localized boron and their use as theranostic agents. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (10B) nuclei that have entered tumor cells to produce highly linear energy transfer (LET) alpha particles and recoil 7Li nuclei (10B [n, α] 7Li). Therefore, the most important part in BNCT is to selectively deliver a large number of 10B to tumor cells and only a small amount to normal tissue. So far, BNCT has been used in more than 2000 cases worldwide, and the efficacy of BNCT in the treatment of head and neck cancer, malignant meningioma, melanoma and hepatocellular carcinoma has been confirmed. We collected and collated clinical studies of second-generation boron delivery agents. The combination of different drugs, the mode of administration, and the combination of multiple treatments have an important impact on patient survival. We summarized the critical issues that must be addressed, with the hope that the next generation of boron delivery agents will overcome these challenges. [ABSTRACT FROM AUTHOR]

Simple Summary: BNCT is a biologically targeted, densely ionizing form of radiation therapy that allows for increased tumor cell kill, while reducing toxicity to surrounding normal tissues. Although BNCT has been investigated in the treatment of head and neck cancers and recurrent brain tumors, its applicability to breast cancer has not been previoulsy investigated. In this review we discuss the physical and biological properties of various boronated compounds, and advantages and challenges associated with the potential use of BNCT in the treatment of breast cancer. BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states. [ABSTRACT FROM AUTHOR]

Systems biology approach, carried out with high-throughput omics technologies, has become a fundamental aspect of the study of complex diseases like cancer. It can molecularly characterize subjects, physiopathological conditions, and interactions, allowing a precise description, to reach personalized medicine. In particular, proteomics, typically performed with liquid chromatography coupled to mass spectrometry, is a powerful tool for systems biology, giving the possibility to perform diagnosis, patient stratification, and prediction of therapy effects. Boron Neutron Capture Therapy (BNCT) is a selective antitumoral radiotherapy based on a nuclear reaction that occurs when Boron-10 (10B) atoms are irradiated by low-energy thermal neutrons, leading to cell death, thanks to the production of high-energy α particles. Since BNCT is recently becoming an important therapy for the treatment of different types of solid tumors such as gliomas, head and neck cancers, and others, it can take advantage of molecular investigation to improve the understanding of effects and mechanisms and so help its clinical applications. In this context, proteomics can provide a better understanding of mechanisms related to BNCT effect, identify potential biomarkers, and individuate differential responses by specific patients, stratifying responders and nonresponders. Another key aspect of BNCT is the study of new potential 10B carriers to improve the selectivity of Boron delivery to tumors and proteomics can be important in this application, studying the effectiveness of new boron delivery agents, including protein-based carriers, also using computational studies that can investigate new molecules, such as boronated monoclonal antibodies, for improving BNCT. [ABSTRACT FROM AUTHOR]

Rodent brain tumor models have been very useful in advancing the treatment of glioblastomas. This review focuses on the four most widely used rodent brain tumor models: the C6, 9L, and F98 rat gliomas, and the GL261 murine glioma. All of these have been used in studies relating to boron neutron capture therapy. The most important of these studies were those using the 9L gliosarcoma, which led to the clinical use of boronophenylalanine, and the F98 glioma, which has been used for the preclinical evaluation of new boron delivery agents and methods of optimizing their delivery. [ABSTRACT FROM AUTHOR]

Photon (X-ray) radiotherapy is the most common treatment used in cancer therapy. However, the exposure of normal tissues and organs at risk to ionising radiation often results in a significant incidence of low-grade adverse side effects, whilst high-grade toxicities also occur at concerningly high rates. As an alternative, boron neutron capture therapy (BNCT) aims to create densely ionising helium and lithium ions directly within cancer cells, thus sparing the surrounding normal cells and tissues but also leading to significantly more effective tumour control than X-rays. Although very promising for patients with recurring and highly invasive tumours, BNCT does not currently have widespread use worldwide, in part due to limited and reliable neutron sources for clinical use. Another limitation is devising strategies leading to the selective and optimal accumulation of boron within the cancer cells. Boronophenylalanine (BPA) is currently the major compound used in BNCT which takes advantage of the amino acid transporter LAT1 that is overexpressed in a number of human cancers. Additionally, there is a lack of in-depth knowledge regarding the impact of BNCT on cellular DNA, and the molecular mechanisms that are responsive to the treatment, which are important in developing optimal therapeutic strategies using BNCT, are unclear. In this review, we highlight the current knowledge of the radiobiology of BNCT acquired from in vitro and in vivo studies, particularly in the context of DNA damage and repair, but also present evidence of established and new boron-containing compounds aimed at enhancing the specificity and effectiveness of the treatment. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a physiologically focused radiation therapy that relies on nuclear capture and fission processes. BNCT is regarded as one of the most promising treatments due to its excellent accuracy, short duration of therapy, and low side effects. The creation of novel boron medicines with high selectivity, ease of delivery, and high boron‐effective load is a current research topic. Herein, boron‐containing carbon dots (BCDs) and their human serum albumin (HSA) complexes (BCDs‐HSA) are designed and synthesized as boron‐containing drugs for BNCT. BCDs (10B: 7.1 wt%) and BCDs‐HSA exhibited excitation‐independent orange fluorescent emission which supported the use of fluorescence imaging for tracking 10B in vivo. The introduction of HSA enabled BCDs‐HSA to exhibit good biocompatibility and increased tumor accumulation. The active and passive targeting abilities of BCDs‐HSA are explored in detail. Subcutaneous RM‐1 tumors and B16‐F10 tumors both significantly decrease with BNCT, which consists of injecting BCDs‐HSA and then irradiating the area with neutrons. In short, this study provides a novel strategy for the delivery of boron and may broaden the perspectives for the design of boron‐containing carbon dots nanomedicine for BNCT. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is radiotherapy that depends on a nuclear reaction between boron-10 (10B) and neutrons. The neutron source has been changing from nuclear reactors to accelerators. Current BNCT using boronophenylalanine (BPA) as the boron compound has been shown to markedly reduce tumor sizes when used to treat recurrent head and neck cancer (HNC); however, early recurrence has been reported. Ultrasound, a safe diagnostic method, in combination with microbubbles, is expected to promote the uptake of BPA into tumor cells. Ultrasound also has the ability to increase the sensitivity of cancer cells to radiotherapy. Therefore, the combination of ultrasound needs to be promoted in order to improve the antitumor efficacy of BNCT for HNC. Boron neutron capture therapy (BNCT) is radiotherapy in which a nuclear reaction between boron-10 (10B) in tumor cells and neutrons produces alpha particles and recoiling 7Li nuclei with an extremely short range, leading to the destruction of the tumor cells. Although the neutron source has traditionally been a nuclear reactor, accelerators to generate neutron beams have been developed and commercialized. Therefore, this treatment will become more widespread. Recurrent head and neck cancer (HNC) close to the body surface is considered a candidate for BNCT using the boron compound boronophenylalanine (BPA) and has been found to be highly responsive to this treatment. However, some cases recur early after the completion of the treatment, which needs to be addressed. Ultrasound is a highly safe diagnostic method. Ultrasound with microbubbles is expected to promote the uptake of BPA into tumor cells. Ultrasound also has the ability to improve the sensitivity of tumor cells to radiotherapy. In addition, high-intensity focused ultrasound may improve the efficacy of BNCT via its thermal and mechanical effects. This review is not systematic but outlines the current status of BPA-based BNCT and proposes plans to reduce the recurrence rate of HNC after BNCT in combination with ultrasound. [ABSTRACT FROM AUTHOR]

Boron neutron capture theory (BNCT) is a binary therapy applied in malignant tumours, resistant to other treatment methods, namely chemotherapy and radiotherapy. One of the main components is Bor-10, a stable isotope that can be inserted in the tumour cells by using specific transporters. Through the use of adequate Boron compounds, that preferably are located in the tumour cells and not in the healthy tissue, Boron neutron capture therapy provides a higher curative potential with minimal toxicity, at the level of normal tissues. In order to obtain a proper tumour control with minimum side effects, 10B increased concentrations should be obtained by selective cumulation within the tumour cells, with an adequate ion gradient between the normal and tumour tissues. Therapeutic effectiveness can be reached by a minimal boron concentration of 20-30 ppm inside the tumour and a tumour/blood and tumour/normal tissues boron concentration gradient of approximately 3. So far, clinical practice has used two main boron delivery agents: sodium borocaptate (Na2B12H11SH) (BSH) and a phenylalanine dihydroxy-boryl derivative, known as Boronophenylalanine (BPA). During the past 20 years, along with the development of new techniques of chemical synthesis and improved knowledge of biological and biochemical requirements for the effectiveness of an agent and ways of boron delivery, a new number of boron delivery agents have appeared in response to the agents up to now. They include: aminoacids, nucleic acid precursors, DNA-binding molecules, porphyrin derivatives, high-molecular- weight delivery agents, macromolecules or nanovehicles such as monoclonal antibodies or monoclonal antibody fragments that bind to tumour epitopes - EGF, VEGF or liposomes, dendrimers, dextrans, polylysine, avidin, folic acid, etc. Next to the identification and study of new boron compounds or new compound combinations, other delivery methods are currently under research seeking to improve the classical intravenous administration and the selective intratumoral binding process as well as the therapeutic index (intraarterial, intratumoral administration, etc). Despite a large number of ongoing studies, a boron compound that fits all the ideal BNCT compound criteria has not yet been identified, especially in terms of tumour selectivity, the ratio of concentrations between the concentration in the tumour cells and the one in the normal cells, the delivery of a proper number of boron atoms in the tumour cells, hydrophilicity and lipophilicity, homogeneous intra-tumour distribution. The development of BNCT boron delivery agents has been initiated approximately 50 years ago and continues to represent at the same time a priority and a difficulty. Several bor-10 boron based pharmaceutical products have been prepared in view of their potential use in BNCT. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy. It combines preferential boron accumulation in tumors and neutron irradiation. Throughout the history of BNCT, huge efforts have been made on the development of more efficient boron-carrying agents. 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. We analyzed examples of newly studied theranostic boron agents that could improve significantly BNCT therapeutic effect. These radiobiological advances intend to solve those limitations and questions that arise during patient treatment in the clinical field, with BNCT and other therapies. An active communication between clinicians, radiobiologists, and all disciplines will improve BNCT for cancer patients, in a cost- and time-effective way. 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. [ABSTRACT FROM AUTHOR]

The ability to selectively kill the tumor sparing the normal tissue is an essential characteristic required for radiotherapy, especially when the tumor is close to very radiosensitive tissues or when it spreads inside vital organs. Boron Neutron Capture Therapy (BNCT) is an experimental radiotherapy that is selective at a cellular level, and for this reason it can be very effective in treating disseminated tumors. It is based on the neutron capture reaction10B(n,α)7Li, with a positive Q-value (2.78 MeV) and with a high cross-section at thermal energies (3840 b). The treatment is delivered by the energy emitted in the reaction and transported by the alpha particles and the recoiling lithium ions; these light ions have a range in tissues comparable with a cell diameter (10 and 6 μm) and thus they deposit their energy with a high stopping power (hundreds of keV/μm) inside the cell where the reaction occurs. [ABSTRACT FROM AUTHOR]

DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α -particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose. [ABSTRACT FROM AUTHOR]

Background Boron neutron capture therapy (BNCT) is a molecular radiation therapy approach based on the 10B (n, α) 7Li nuclear reaction in cancer cells. In BNCT, delivery of 10B in the form of 4-borono-phenylalanine conjugated with fructose (BPA-fr) to the cancer cells is important. The PET tracer 4-borono-2-18F-fluoro-phenylalanine (FBPA) has been used to predict the accumulation of BPA-fr before BNCT. Purpose To determine the biodistribution and dosimetric parameters in 18F-BPA PET/CT studies. Material and Methods Human biokinetic data were obtained during clinical 18F-BPA PET studies between February and June 2015 at one institution. Nine consecutive patients were studied prospectively. The internal radiation dose was calculated on the basis of radioactivity data from blood, urine, and normal tissue of the heart, liver, spleen, kidney, and other parts of the body at each time point using OLINDA/EXM1.1 program. We compared our calculations with published 18F-FDG data. Results Adult patients (3 men, 3 women; age range, 28-68 years) had significantly smaller absorbed doses than pediatric patients (3 patients; age range, 5-12 years) ( P = 0.003). The mean effective dose was 57% lower in adult patients compared with pediatric patients. Mean effective doses for 18F-BPA were 25% lower than those for 18F-FDG presented in International Commission of Radiation Protection (ICRP) publication 106. Conclusion We found significant differences in organ absorbed doses for 18F-BPA against those for 18F-FDG presented in ICRP publication 106. Mean effective doses for 18F-BPA were smaller than those for 18F-FDG in the publication by 0.5-38% (mean difference, 25%). [ABSTRACT FROM AUTHOR]

Background: Boron neutron capture therapy (BNCT) is a unique particle radiation therapy based on the nuclear capture reactions in boron-10. We developed a novel boron-10 containing sodium borocaptate (BSH) derivative, 1-amino-3-fluorocyclobutane-1-carboxylic acid (ACBC)-BSH. ACBC is a tumor selective synthetic amino acid. The purpose of this study was to assess the biodistribution of ACBC-BSH and its therapeutic efficacy following Boron Neutron Capture Therapy (BNCT) of the F98 rat glioma.Methods: We evaluated the biodistribution of three boron-10 compounds, ACBC-BSH, BSH and boronophenylalanine (BPA), in vitro and in vivo, following intravenous (i.v.) administration and intratumoral (i.t.) convection-enhanced delivery (CED) in F98 rat glioma bearing rats. For BNCT studies, rats were stratified into five groups: untreated controls, neutron-irradiation controls, BNCT with BPA/i.v., BNCT with ACBC-BSH/CED, and BNCT concomitantly using BPA/i.v. and ACBC-BSH/CED.Results: In vitro, ACBC-BSH attained higher cellular uptake F98 rat glioma cells compared with BSH. In vivo biodistribution studies following i.v. administration and i.t. CED of ACBC-BSH attained significantly higher boron concentrations than that of BSH, but much lower than that of BPA. However, following convection enhanced delivery (CED), ACBC-BSH attained significantly higher tumor concentrations than BPA. The i.t. boron-10 concentrations were almost equal between the ACBC-BSH/CED group and BPA/i.v. group of rats. The tumor/brain boron-10 concentration ratio was higher with ACBC-BSH/CED than that of BPA/i.v. group. Based on these data, BNCT studies were carried out in F98 glioma bearing rats using BPA/i.v. and ACBC-BSH/CED as the delivery agents. The corresponding mean survival times were 37.4 ± 2.6d and 44.3 ± 8.0d, respectively, and although modest, these differences were statistically significant.Conclusions: Our findings suggest that further studies are warranted to evaluate ACBC-BSH/CED as a boron delivery agent. [ABSTRACT FROM AUTHOR]

Boron Neutron Capture Therapy (BNCT) is a radiation science which is emerging as a hopeful tool in treating cancer, by selectively concentrating boron compounds in tumour cells and then subjecting the tumour cells to epithermal neutron beam radiation. BNCT bestows upon the nuclear reaction that occurs when Boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield a particles (Helium-4) and recoiling lithium-7 nuclei. A large number of 10 Boron (10B) atoms have to be localized on or within neoplastic cells for BNCT to be effective, and an adequate number of thermal neutrons have to be absorbed by the 10B atoms to maintain a lethal 10B (n, a) lithium-7 reaction. The most exclusive property of BNCT is that it can deposit an immense dose gradient between the tumour cells and normal cells. BNCT integrates the fundamental focusing perception of chemotherapy and the gross anatomical localization proposition of traditional radiotherapy. [ABSTRACT FROM AUTHOR]

Background. We previously demonstrated the therapeutic success of sequential boron neutron capture therapy (Seq-BNCT) in the hamster cheek pouch oral cancer model. It consists of BPA-BNCT followed by GB-10-BNCT 24 or 48 hours later. Additionally, we proved that tumor blood vessel normalization with thalidomide prior to BPA-BNCT improves tumor control. The aim of the present study was to evaluate the therapeutic efficacy and explore potential boron microdistribution changes in Seq-BNCT preceded by tumor blood vessel normalization. Material and Methods. Tumor bearing animals were treated with thalidomide for tumor blood vessel normalization, followed by Seq-BNCT (Th+ Seq-BNCT) or Seq-Beam Only (Th+ Seq-BO) in the window of normalization. Boron microdistribution was assessed by neutron autoradiography. Results. Th+ Seq-BNCT induced overall tumor response of 100%, with 87 (4)% complete tumor response. No cases of severe mucositis in dose-limiting precancerous tissue were observed. Differences in boron homogeneity between tumors pre-treated and not pre-treated with thalidomide were observed. Conclusion. Th+ Seq-BNCT achieved, for the first time, response in all treated tumors. Increased homogeneity in tumor boron microdistribution is associated to an improvement in tumor control. [ABSTRACT FROM AUTHOR]

In an investigation by the Swedish Cancer Society, an expert group described the present status, critical issues and future aspects and potentials for each of nine major areas of radiation therapy research. This report deals with radiation therapy using activation of stable nuclides. [ABSTRACT FROM AUTHOR]

Simple Summary: The non-surgical treatment of cutaneous and/or subcutaneous melanoma lesions involves a multitude of local treatments, including radiotherapy. This is often used when other local methods fail, and there are currently no clear guidelines or evidence-based recommendations to support its use in this setting. This review, collecting the retrospective and prospective experiences on radiotherapy alone or in combination with other methods, aims to provide a scenario of the possible advantages and disadvantages related to its use in the treatment of skin/subcutaneous melanoma lesions. Malignant melanoma frequently develops cutaneous and/or subcutaneous metastases during the course of the disease. These may present as non-nodal locoregional metastases (microsatellite, satellite, or in-transit) included in stage III or as distant metastases in stage IV. Their presentation is heterogeneous and associated with significant morbidity resulting from both disease-related functional damage and treatment side effects. The standard treatment is surgical excision, whereas local therapies or systemic therapies have a role when surgery is not indicated. Radiotherapy can be used in the local management of ITM, subcutaneous relapses, or distant metastases to provide symptom relief and prolong regional disease control. To increase the local response without increasing toxicity, the addition of hyperthermia and intralesional therapies to radiotherapy appear to be very promising. Boron neutron capture therapy, based on nuclear neutron capture and boron isotope fission reaction, could be an alternative to standard treatments, but its use in clinical practice is still limited. The potential benefit of combining radiotherapy with targeted therapies and immunotherapy has yet to be explored in this lesion setting. This review explores the role of radiotherapy in the treatment of cutaneous and subcutaneous lesions, its impact on outcomes, and its association with other treatment modalities. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is becoming one of the most promising radiotherapies for aggressive cancers, but the detailed cellular mechanisms of BNCT remain largely underexplored. Solid tumors are composed of heterogeneous cell populations, which create a 3-dimensional complicated microenvironment for tumor progression. To recapture the influences of the microenvironment on BNCT efficacy, we applied a self-assembly 3D cell culture system with two different types of pancreatic cancer cells. In contrast to previous findings with γ-ray exposure, we found that the 3D architecture of pancreatic tumor can facilitate the susceptibility of cancer cells to BNCT, as compared to 2D tissue structure; a computer simulation model was established to further confirm this unexpected finding. These outcomes can contribute to better understanding of the radiobiology of BNCT, and the developed models may facilitate the recent development in personalized radiotherapy. Pancreatic cancer is a leading cause of cancer death, and boron neutron capture therapy (BNCT) is one of the promising radiotherapy techniques for patients with pancreatic cancer. In this study, we evaluated the biological effectiveness of BNCT at multicellular levels using in vitro and in silico models. To recapture the phenotypic characteristic of pancreatic tumors, we developed a cell self-assembly approach with human pancreatic cancer cells Panc-1 and BxPC-3 cocultured with MRC-5 fibroblasts. On substrate with physiological stiffness, tumor cells self-assembled into 3D spheroids, and the cocultured fibroblasts further facilitated the assembly process, which recapture the influence of tumor stroma. Interestingly, after 1.2 MW neutron irradiation, lower survival rates and higher apoptosis (increasing by 4-fold for Panc-1 and 1.5-fold for BxPC-3) were observed in 3D spheroids, instead of in 2D monolayers. The unexpected low tolerance of 3D spheroids to BNCT highlights the unique characteristics of BNCT over conventional radiotherapy. The uptake of boron-containing compound boronophenylalanine (BPA) and the alteration of E-cadherin can partially contribute to the observed susceptibility. In addition to biological effects, the probability of induced α-particle exposure correlated to the multicellular organization was speculated to affect the cellular responses to BNCT. A Monte Carlo (MC) simulation was also established to further interpret the observed survival. Intracellular boron distribution in the multicellular structure and related treatment resistance were reconstructed in silico. Simulation results demonstrated that the physical architecture is one of the essential factors for biological effectiveness in BNCT, which supports our in vitro findings. In summary, we developed in vitro and in silico self-assembly 3D models to evaluate the effectiveness of BNCT on pancreatic tumors. Considering the easy-access of this 3D cell-assembly platform, this study may not only contribute to the current understanding of BNCT but is also expected to be applied to evaluate the BNCT efficacy for individualized treatment plans in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, within the research community, exosomes, transporters of bioactive molecules involved in many signalling pathways and cell-to-cell communication with the capacity to alter the tumour microenvironment, have been attracting increasing interest among oncologists. These molecules can play multiple roles, e.g., as useful biomarkers in diagnosis, modulators of the immune system, promoters of the formation of the pre-metastatic niches and cancer metastasis and carriers of substances or factors with anticancer properties. This review focuses on the use of exosomes as a novel therapeutic strategy for cancer treatment. Particularly, it highlights the potential of exosomes as carriers of stem cell differentiation stage factors (SCDSFs) for "cell reprogramming" therapy, a promising research field on which we have reported previously. Here, the main characteristics of this treatment and the advantages that can be obtained using mesenchymal stem cell-derived exosomes up-loaded with the SCDSFs as carriers of these factors are also discussed. Exosomes are nano-vesicle-shaped particles secreted by various cells, including cancer cells. Recently, the interest in exosomes among cancer researchers has grown enormously for their many potential roles, and many studies have focused on the bioactive molecules that they export as exosomal cargo. These molecules can function as biomarkers in diagnosis or play a relevant role in modulating the immune system and in promoting apoptosis, cancer development and progression. Others, considering exosomes potentially helpful for cancer treatment, have started to investigate them in experimental therapeutic trials. In this review, first, the biogenesis of exosomes and their main characteristics was briefly described. Then, the capability of tumour-derived exosomes and oncosomes in tumour microenvironments (TMEs) remodelling and pre-metastatic niche formation, as well as their interference with the immune system during cancer development, was examined. Finally, the potential role of exosomes for cancer therapy was discussed. Particularly, in addition, their use as carriers of natural substances and drugs with anticancer properties or carriers of boron neutron capture therapy (BNCT) and anticancer vaccines for immunotherapy, exosomes as biological reprogrammers of cancer cells have gained increased consensus. The principal aspects and the rationale of this intriguing therapeutic proposal are briefly considered. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most lethal tumor among all cancers with a median overall survival of 14 months and to develop new effective therapies is an urgent issue. Boron Neutron Capture Therapy (BNCT) is a unique radiation therapy that uses boron compounds and thermal neutrons. This study is aimed to investigate whether glioma stem cells, which is resistant to chemo-radiation therapy, take up a boron compound, p-boronophenylalanine (BPA) or not. Both in vitro and in vivo studies, more glioma stem like cells took up BPA compared with the differentiated glioma cells and indicated that BNCT can target to kill GSCs and be an effective therapy for malignant glioma. As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5–9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2–4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT. [ABSTRACT FROM AUTHOR]

Simple Summary: The biological pathways underlying glioblastoma malignancy and radioresistance are still unclear. In this review, we describe the role of the hypoxic microenvironment and SRC proto-oncogene non-receptor tyrosine kinase in the activation of radioresistance and invasion pathways of glioblastoma. We also highlight the hypoxia- and ionizing radiation-induced infiltration, providing updated evidences on the involvement of SRC in these processes. Optimizing radiotherapy and identifying druggable molecular players are crucial steps to improve current glioblastoma therapeutic strategies. Advances in functional imaging are supporting neurosurgery and radiotherapy for glioblastoma, which still remains the most aggressive brain tumor with poor prognosis. The typical infiltration pattern of glioblastoma, which impedes a complete surgical resection, is coupled with a high rate of invasiveness and radioresistance, thus further limiting efficient therapy, leading to inevitable and fatal recurrences. Hypoxia is of crucial importance in gliomagenesis and, besides reducing radiotherapy efficacy, also induces cellular and molecular mediators that foster proliferation and invasion. In this review, we aimed at analyzing the biological mechanism of glioblastoma invasiveness and radioresistance in hypoxic niches of glioblastoma. We also discussed the link between hypoxia and radiation-induced radioresistance with activation of SRC proto-oncogene non-receptor tyrosine kinase, prospecting potential strategies to overcome the current limitation in glioblastoma treatment. [ABSTRACT FROM AUTHOR]

While conventional radiation therapy uses white X-rays that consist of a mixture of X-ray waves with various energy levels, a monochromatic X-ray (monoenergetic X-ray) has a single energy level. Irradiation of high-Z elements such as gold, silver or gadolinium with a synchrotron-generated monochromatic X-rays with the energy at or higher than their K-edge energy causes a photoelectric effect that includes release of the Auger electrons that induce DNA damage—leading to cell killing. Delivery of high-Z elements into cancer cells and tumor mass can be facilitated by the use of nanoparticles. Various types of nanoparticles containing high-Z elements have been developed. A recent addition to this growing list of nanoparticles is mesoporous silica-based nanoparticles (MSNs) containing gadolinium (Gd–MSN). The ability of Gd–MSN to inhibit tumor growth was demonstrated by evaluating effects of irradiating tumor spheroids with a precisely tuned monochromatic X-ray. [ABSTRACT FROM AUTHOR]

Radiation therapy has made tremendous progress in oncology over the last decades due to advances in engineering and physical sciences in combination with better biochemical, genetic and molecular understanding of this disease. Local delivery of optimal radiation dose to a tumor, while sparing healthy surrounding tissues, remains a great challenge, especially in the proximity of vital organs. Therefore, imaging plays a key role in tumor staging, accurate target volume delineation, assessment of individual radiation resistance and even personalized dose prescription. From this point of view, radiotherapy might be one of the few therapeutic modalities that relies entirely on high-resolution imaging. Magnetic resonance imaging (MRI) with its superior soft-tissue resolution is already used in radiotherapy treatment planning complementing conventional computed tomography (CT). Development of systems integrating MRI and linear accelerators opens possibilities for simultaneous imaging and therapy, which in turn, generates the need for imaging probes with therapeutic components. In this review, we discuss the role of MRI in both external and internal radiotherapy focusing on the most important examples of contrast agents with combined therapeutic potential. [ABSTRACT FROM AUTHOR]