Development Of Boron Neutron Capture Therapy Research Articles

Boron Neutron Capture Therapy: Current Status and Challenges.

Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (4He) and recoil lithium particles (7Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.

Boron neutron capture therapy in clinical application:Progress and prospect

<p indent="0mm">Boron neutron capture therapy (BNCT) is an emerging radiotherapeutic modality aimed at selectively concentrating boron compounds in tumor cells and then subjecting the tumor cells to neutron beam radiation. Treatment with BNCT is based on the nuclear capture and fission reactions that occur when nonradioactive boron-10 (¹⁰B) is irradiated with neutrons to yield an alpha particle (helium, ⁴He) and a recoiling lithium-7 (⁷Li) nuclei. The ⁴He particle has a range of <sc>9 μm</sc> and the ⁷Li particle <sc>5 μm</sc> in tissue. In theory, the short range of this reaction limits the damage to malignant cells while sparing adjacent normal cells. The development of BNCT is still constrained by the progress in developing boron delivery agents with a high tumor uptake, low normal tissue uptake, and optimizing the dosing paradigms and quantitative estimation of the ¹⁰B concentrations. It is widely recognized that the second generation boron-containing agents, sodium borocaptate (BSH) and boronophenylalanine (BPA), are less than ideal. New and more effective boron-containing agents are urgently required for clinical use to deliver the requisite amounts of boron to tumor cells. The delivery of boron-containing agent can also be optimized to improve cancer cell uptake and subcellular distribution. Additionally, it is crucial to design high intensity neutron sources and establish hospital-based BNCT. Compared with nuclear reactors, accelerator-based neutron sources are more realistic to be applied in clinical practice. In future, the critical issues regarding novel boron-containing agents, the appropriate delivery strategies, and neutron sources of BNCT for clinical use must be addressed. Two clinical trials with newly diagnosed glioblastoma have been reported, BNCT alone after surgery provided a mean survival time of 17.7 and <sc>19.5 months</sc> respectively. The survival outcomes were good as compared to the current standard of care which is post-operation fractionated radiotherapy with concomitant and adjuvant TMZ. Several clinical studies of BNCT in the treatment of recurrent head and neck cancer have been reported, with high response rate and acceptable toxicity. To date, BNCT has been clinically evaluated as an alternative to conventional radiotherapy for the treatment of several tumor types, including newly diagnosed glioblastoma, recurrent glioma, recurrent head and neck tumors, meningioma, malignant melanoma, and liver metastasis. Recently, accelerator-based neutron source has been used in clinical trials for recurrent malignant gliomas and head &amp; neck cancers. Although initial results with BNCT are promising, high-quality prospective clinical trials are still lacking. Well-designed phase II/III clinical research is necessary to define the efficacy and safety of BNCT in various tumor types. Meanwhile, studies comparing the outcomes of BNCT with other standards of care are needed for the further development of BNCT. Based on the previous studies, the BNCT clinical trials in glioblastoma can be initiated with newly diagnosed glioblastoma patients. For other tumor types, late-stage patients with recurrent or metastatic disease after the first-line treatment might be recruited. Last but not the least, in the era of comprehensive treatment for malignant tumor, it is necessary to explore the combined treatment mode of BNCT. For the future research, BNCT may be coupled with a variety of anti-tumor modalities, including traditional photon radiotherapy, immunotherapy, targeted therapy and chemotherapy. It is also possible to explore a variety of drug delivery methods to improve the uptake of boron-containing agents by tumor sites. Multidisciplinary model is needed to jointly promote BNCT to become a routine clinical treatment modality.

Current Status of Accelerator-Based Boron Neutron Capture Therapy (BNCT)

Clinical studies of boron neutron capture therapy (BNCT) have been conducted using thermal and epithermal neutron beams generated from research reactors. Considering the spread and development of BNCT, it has been desired to realize BNCT using an accelerator-based neutron source that can be installed in medical institutions. To date, the accelerator-based BNCT has been developed by combining various accelerators such as a cyclotron and a linear accelerator with neutron generation targets. In Japan, the world's first treatment system using a combination of a cyclotron and a beryllium target has received manufacturing and marketing approval as a medical device. In June 2020, BNCT insurance medical treatment was started at medical institutions. Currently, BNCT is being performed for cases of locally unresectable recurrent or unresectable advanced head and neck cancer. In this paper, it is shown that the history of reactor-based BNCT and the current development status and future prospects of the accelerator-based BNCT, which has been carried out in advance in Japan.

In Vivo Total Dose Analysis in Mice for BNCT Trial TRIGA Kartini Research Reactor Based Using PHITS

Boron neutron capture therapy (BNCT) is an effective radiotherapy modality to kill cancer. BNCT can selectively kill cancer cells without damaging the healthy tissue around it by using alpha particle and lithium ion from the reaction of 10B(n,α)7Li. These particles have a track of more or less 5 to 9 μm which is the same as the cell diameter. In order to support the development of BNCT in Indonesia an in vivo simulation is performed in a simple mouse geometry containing a 4T1 breast cancer characteristic treated with BNCT using PHITS program. The Neutron source that was used in this simulation was based on TRIGA Kartini Research Reactor. The boron compound concentration in the tumor was varied from 20 ppm up to 90 ppm, and then the total dose was calculated in the mice. Total dose that the tumor received was 0.0161, 0.0168, 0.0175, 0.0182, 0.0185, 0.0188, 0.019, and 0.0191 Gy-Eq/s, respectively and the irradiation time to reach 50 Gy was 51, 50, 48, 46, 45, 45, 44, 44, 40 minutes respectively. This shows that the higher the concentration of boron compound in the tumor the higher the dose that mice received and irradiation time was decreased with the increase of the boron compound concentration.

Radiation accompanying the absorption of 2-MeV protons in various materials

For the development of boron neutron-capture therapy of malignant tumors, a source of epithermal neutrons on the basis of a tandem accelerator with a vacuum insulation and a lithium target was created and launched. With the aim of optimizing the neutron-producing target, various structure materials were irradiated with a proton beam. The results obtained bymeasuring the dose rate and radiation spectrum upon the absorption of 2-MeV protons are presented, and the choice of tantalum for an optimum material of the target substrate was explained.

Neutron medical treatment of tumours — a survey of facilities

Neutron therapy has two branches: Fast Neutron Therapy (FNT) and Boron Neutron Capture Therapy (BNCT). The mean neutron energies used for FNT range from 2 MeV to 25 MeV whereas the maximum energy for BNCT is about 10 keV. Neutron generators for FNT have been cyclotrons, accelerators and reactors, whereas BNCT is so far bound to reactors. Both therapies use the effects of high-LET radiation (secondary recoil protons and alpha particles, respectively) and can attack otherwise radioresistant tumours, however, with the hazard of adverse effects for irradiated healthy tissue.FNT has been administered to about 30,000 patients world-wide. From formerly 40 facilities, only eight are operational or stand-by today. The reasons for this development have been, on the one hand, related to technical and economical conditions; on the other hand, strong side effects and insufficient proof of clinical results in the early years as well as increasing competition with new clinical methods have reduced patient numbers. In fact, strict observations of indications, appropriate therapy-planning including low-LET radiation, and consequent treatment of side effects have lead to remarkable results in the meantime.BNCT initially was developed for the treatment of extremely aggressive forms of brain tumour, taking advantage of the action of the blood-brain-barrier which allows for a boronated compound to be selectively enriched in tumour cells. Meanwhile, also malignant melanoma (MM) and Head-and-Neck (H&T) tumours are treated because of their relative radioresistance. At present, epithermal beams with sufficient flux are available only at two facilities. Existing research reactors were indispensable in the development of BNCT, but are to be replaced by hospital-based epithermal neutron sources. Clinical results indicate significantly increased survival times, but the number of patients ever treated is still below 1,000.3D-dose calculation systems have been developed at several facilities and guarantee a high safety for both therapies, FNT and BNCT.

Building of scientific information system for sustainable development of BNCT in Bulgaria

Building a boron neutron capture therapy (BNCT) facility is foreseen within the reconstruction of the Research Reactor IRT (IRT) of the Institute for Nuclear Research and Nuclear Energy of the Bulgaria Academy of Sciences (INRNE). The development of BNCT at IRT plays a very significant role in the plan for sustainable application of the reactor. A centralized scientific information system on BNCT is being built at the INRNE with the purpose to collect and sort new information as knowledge accumulated during more than thirty years history of BNCT. This BNCT information system will help the creation and consolidation of a well informed and interconnected interdisciplinary team of physicists, chemists, biologists, and radio-oncologists for establishing BNCT cancer treatment in Bulgaria. It will strengthen more intensive development of the national network as well as its enlargement to the Balkan region countries. Furthermore, to acquaint the public at large with the opportunity for BNCT cancer treatment will be addressed. Human, social, and economics results due to BNCT for many patients from Balkan region are expected.

A critical assessment of boron target compounds for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) has undergone dramatic developments since its inception by Locher in 1936 and the development of nuclear energy during World War II. The ensuing Cold War spawned the entirely new field of polyhedral borane chemistry, rapid advances in nuclear reactor technology and a corresponding increase in the number to reactors potentially available for BNCT. This effort has been largely oriented toward the eradication of glioblastoma multiforme (GBM) and melanoma with reduced interest in other types of malignancies. The design and synthesis of boron-10 target compounds needed for BNCT was not channeled to those types of compounds specifically required for GBM or melanoma. Consequently, a number of potentially useful boron agents are known which have not been biologically evaluated beyond a cursory examination and only three boron-10 enriched target species are approved for human use following their Investigational New Drug classification by the US Food and Drug Administration; BSH, BPA and GB-10. All ongoing clinical trials with GBM and melanoma are necessarily conducted with one of these three species and most often with BPA. The further development of BNCT is presently stalled by the absence of strong support for advanced compound evaluation and compound discovery driven by recent advances in biology and chemistry. A rigorous demonstration of BNCT efficacy surpassing that of currently available protocols has yet to be achieved. This article discusses the past history of compound development, contemporary problems such as compound classification and those problems which impede future advances. The latter include means for biological evaluation of new (and existing) boron target candidates at all stages of their development and the large-scale synthesis of boron target species for clinical trials and beyond. The future of BNCT is bright if latitude is given to the choice of clinical disease to be treated and if a recognized study demonstrating improved efficacy is completed. Eventually, BNCT in some form will be commercialized.