This paper takes a broad lens concerning the development and progress of Boron Neutron Capture Therapy (BNCT) in the past 50 years. BNCT has proven to be a viable approach to treating high-grade gliomas and other brain and neck tumors in situations where other treatment options have failed. Visibility of BNCT as a treatment has been limited because of the complex facilities required to carry out the process; however, this paper analyzes the future for commercializing BNCT for treatment and improving access and safety for its use.
Boron Neutron Capture Therapy is a method to target and destroy tumors in the head and neck region, most commonly glioblastomas in the brain. BNCT mainly functions by delivering boron particles to tumor cells and irradiating the region with neutrons to kill the tumor cells. When Boron-10 isotopes are irradiated by neutrons, the reaction results in a high energy alpha particle and a recoiling Lithium-7 molecule being released. Alpha particles have a short pathlength, which means their destructive properties are limited to tumor cells.  Thus, in theory, if boron particles are selectively delivered to tumor cells, irradiation can allow alpha particles to destroy only tumor cells while sparing healthy cells. This treatment option is contingent on two processes. First, the boron must be selectively delivered to tumor cells and second, the neutrons used for irradiation must be administered in the optimal dosage to kill tumor cells and spare healthy cells. The future of BNCT is one where patients with head and neck tumors have the potential to be cancer-free in a single BNCT session. This paper will review the history of BNCT and evaluate the success of different approaches to optimize the two key processes for commercialization.
History and Methodology
BNCT was identified for its potential almost immediately after the discovery of the neutron by G.L. Locher in 1936. However, only by 1951 were clinical trials in place at MIT and Massachusetts General Hospital (MGH) . These studies utilized fission reaction beams of thermal neutrons. However, this method proved to be inadequate for penetration. This limitation led to clinical trials being paused for decades until the early 1990s. When the trials restarted, higher energy neutrons were utilized and penetration into the brain was optimized to reach tumors. Extensive clinical trials have proven two drugs to be the most effective delivery methods to date. However, limitations within each still exist. The first drug is boronophenylalanine (BPA), synthesized by Snyder, while the second drug is sodium borocaptate (BSH), first used by Hatanaka in Japan . Both drugs have been criticized because of their variability in tumor uptake. Variability in tumor uptake can cause treatment to be ineffective for some while successful for others, with no metric to control this success rate. The most favorable results of BNCT using BPA and BSH have been achieved at the Kyoto University Research Reactor Institute (KURRI) . Out of the 49 patients with unresectable tumors at the institute, 80% had failed chemotherapy. After BNCT, the one-year survival rate rose to 58% for those with unresectable tumors and 41% for those with recurrent tumors . The clinical trials at KURRI utilized a mixed dosage of BPA and BSH, allowing the treatment to be maximally effective. Even in cases where chemotherapy is a viable treatment option, other studies at KURRI have proven BNCT to be competitive with chemotherapy while only requiring a single BNCT session. Thus, the future of BNCT likely falls in filling the niche of patients where surgery and chemotherapy have already failed. However, since one of the underlying conditions for the success of BNCT is selective delivery of a lethal dosage to tumor cells, the next section will focus on recent developments in the delivery options for boron-10 to tumor cells.
Development in Delivery Methods
The conditions for a delivery agent for BNCT are that they must have a low inherent toxicity, high tumor uptake, and easy clearance from the normal blood tissue . The delivery of the agent must also easily pass the blood-brain barrier which is the selective layer of endothelial cells that regulates solutes in the blood from passing into the fluid of the central nervous system. Finding a delivery agent that can cross this barrier is a major impediment to BNCT research . BPA’s mechanism for targeting tumor cells is upregulated amino acid transporters in cancer cells. The rapid proliferation rate of cancer and tumor cells causes them to require more amino acids to keep pace with cell growth. To provide the necessary levels of amino acids, the tumor cells upregulate amino acid transporters, creating a prime target for BPA. New studies use the same mechanism of upregulated receptors to target tumor cells. For instance, one study by Backer focuses on using peptide ligands to target one of two specific receptors: either the vascular endothelial growth factor (VEGFR) or the epidermal growth factor receptor (EGFR) . However, the issue with the targeting of VEGFR and EGFR is the requirement of multiple rounds of BNCT to effectively reach all tumor cells. There are still multiple other different strategies for delivery being investigated right now. One interesting study in effect is the use of boron nitride nanotubes (BNNT) as delivery mechanisms with folate-receptor functionalized coating for the BNNTs. Folate receptors have been proven to be over-expressed in tumor cells in multiple studies because of folate’s key role in DNA replication and cell division. The BNNT molecules can travel easily through the blood while the functionalized folate coating allows the BNNT to only reach tumor cells . Other current studies for optimizing boron delivery use nucleotides, amino acids, and liposomes. Despite these studies, BPA and BSH are the only drugs that have been approved for clinical use in the past 50 years .
Developments in Neutron Supply
Another impediment for using BNCT to combat brain tumors is the complex neutron supply it requires, which is unsuitable for implementation in hospitals due to safety concerns. Fission reactors are the current neutron source of choice because of their capability to produce high energy neutrons for the boron reactions. 8 reactor facilities have been built in the Americas, Europe, and Asia for clinical use in BNCT . These reactors have safety issues with radiation, barring them from being viable in urban settings or hospitals. However, in China, scientists have constructed a reactor designed for neutron capture therapy use, and it is suited for urban settings because of its use of low power core neutrons. Accelerator-based neutron sources are a new development that produce low-intensity neutron fluxes . While the low intensity of accelerator sources makes it less competitive than fission sources, due to a decreased ability of the neutrons to reach the tumor targets, accelerator-based neutron sources are more compact, less expensive, and safer.
Future of BNCT
Overall, Boron Neutron Capture Therapy is a treatment with high potential for helping individuals in cases where chemotherapy or re-irradiation has failed. However, a few key issues must be addressed before BNCT can be successful on a large scale. Progress has been inhibited because of a lack of communication between different institutions doing BNCT research. BNCT is still considered experimental because of a lack of standardization for radiation calibration or treatment plans . Currently, there is no consensus on dosage recommendations. To conduct large scale clinical trials, there needs to be dosage uniformity across institutions conducting BNCT research . Furthermore, BNCT cannot reach deep-seated tumors in the brain currently, limiting its usage to shallow glioblastomas. There is also no mechanism to predict which patients are most likely to respond favorably to BNCT treatment. However, despite current setbacks, the optimization of delivery techniques and commercialization of neutron sources can provide major progress for widespread clinical trials. With these developments, BNCT can fulfill its full potential of helping patients with brain tumors where other methods have failed.
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