neutron capture therapy of cancer neutron capture therapy of cancer neutron capture therapy (nct) is a type of radiotherapy for treating locally invasive malignant tumors such as primary brain tumors, recurrent cancers of the head and neck region, and cutaneous and extracutaneous melanomas. it is a two-step process: first, the patient is injected with a tumor-localizing drug containing the stable isotope boron-10 (10b), which has a high propensity to capture low energy "thermal" neutrons. the neutron cross section of 10b (3,837 barns) is 1,000 times more than that of other elements, such as nitrogen, hydrogen, or oxygen, that occur in tissue. in the second step, the patient is radiated with epithermal neutrons, the sources of which in the past have been nuclear reactors and now are accelerators that produce higher energy epithermal neutrons. after losing energy as they penetrate tissue, the resultant low energy "thermal" neutrons are captured by the 10b atoms. the resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up enough 10b. neutron capture therapy of cancera. bnct is based on the neutron capture and decay reactions that occur when boron-10 is irradiated with low-energy (0.0025 ev) thermal neutrons. the resulting 10b(n,α)7li capture reaction yields high linear energy transfer (let) α particles (stripped down helium nuclei ) and recoiling lithium-7 (7li) atoms. b. the short range (5-9 μm) of the α particles limits the destructive effects to the boron-containing cells. in theory, bnct can selectively destroy malignant cells while sparing adjacent normal tissue if the requisite amounts of 10b and neutrons are delivered to the tumor cells. reprinted from barth rf, mi p, yang w (june 2018). "boron delivery agents for neutron capture therapy of cancer". cancer communications. 38 (1): 35. doi:10.1186/s40880-018-0299-7. pmc 6006782. pmid 29914561).specialtyoncology all clinical experience with nct to date is with boron-10; hence this method is known as boron neutron capture therapy (bnct). use of another non-radioactive isotope, such as gadolinium, has been limited to experimental animal studies and has not been done clinically. bnct has been evaluated as an alternative to conventional radiation therapy for malignant brain tumors such as glioblastomas, which presently are incurable, and more recently, locally advanced recurrent cancers of the head and neck region and, much less often, superficial melanomas mainly involving the skin and genital region. boron neutron capture therapy history james chadwick discovered the neutron in 1932. shortly thereafter, h. j. taylor reported that boron-10 nuclei had a high propensity to capture low energy "thermal" neutrons. this reaction causes nuclear decay of the boron-10 nuclei into helium-4 nuclei (alpha particles) and lithium-7 ions. in 1936, g.l. locher, a scientist at the franklin institute in philadelphia, pennsylvania, recognized the therapeutic potential of this discovery and suggested that this specific type of neutron capture reaction could be used to treat cancer. william sweet, a neurosurgeon at the massachusetts general hospital, first suggested the possibility of using bnct to treat malignant brain tumors to evaluate bnct for treatment of the most malignant of all brain tumors, glioblastoma multiforme (gbms), using borax as the boron delivery agent in 1951. a clinical trial subsequently was initiated by lee farr using a specially constructed nuclear reactor at the brookhaven national laboratory in long island, new york, u.s.a. another clinical trial was initiated in 1954 by sweet at the massachusetts general hospital using the research reactor at the massachusetts institute of technology (mit) in boston. a number of research groups worldwide have continued the early ground-breaking clinical studies of sweet and farr, and subsequently the pioneering clinical studies of hiroshi hatanaka (畠中洋) in the 1960s, to treat patients with brain tumors. since then, clinical trials have been done in a number of countries including japan, the united states, sweden, finland, the czech republic, and argentina. after the nuclear accident at fukushima (2011), the clinical program there transitioned from a reactor neutron source to accelerators that would produce high energy neutrons that become thermalized as they penetrate tissue. basic principles neutron capture therapy is a binary system that consists of two separate components to achieve its therapeutic effect. each component in itself is non-tumoricidal, but when combined they can be highly lethal to cancer cells. 1) boron compound (b) is selectively absorbed by cancer cell(s). 2) neutron beam (n) is aimed at cancer site. 3) boron absorbs neutron. 4) boron disintegrates emitting cancer-killing radiation. bnct is based on the nuclear capture and decay reactions that occur when non-radioactive boron-10, which makes up approximately 20% of natural elemental boron, is irradiated with neutrons of the appropriate energy to yield excited boron-11 (11b*). this undergoes radioactive decay to produce high-energy alpha particles (4he nuclei) and high-energy lithium-7 (7li) nuclei. the nuclear reaction is: 10b + nth → *→ α + 7li + 2.31 mev both the alpha particles and the lithium nuclei produce closely spaced ionizations in the immediate vicinity of the reaction, with a range of 5–9 µm. this approximately is the diameter of the target cell, and thus the lethality of the capture reaction is limited to boron-containing cells. bnct, therefore, can be regarded as both a biologically and a physically targeted type of radiation therapy. the success of bnct is dependent upon the selective delivery of sufficient amounts of 10b to the tumor with only small amounts localized in the surrounding normal tissues. thus, normal tissues, if they have not taken up sufficient amounts of boron-10, can be spared from the neutron capture and decay reactions. normal tissue tolerance, however, is determined by the nuclear capture reactions that occur with normal tissue hydrogen and nitrogen. a wide variety of boron delivery agents have been synthesized. the first, which has mainly been used in japan, is a polyhedral borane anion, sodium borocaptate or bsh (na2b12h11sh), and the second is a dihydroxyboryl derivative of phenylalanine, called boronophenylalanine or bpa. the latter has been used in many clinical trials. following administration of either bpa or bsh by intravenous infusion, the tumor site is irradiated with neutrons, the source of which, until recently, has been specially designed nuclear reactors and now is neutron accelerators. until 1994, low-energy (< 0.5 ev) thermal neutron beams were used in japan and the united states, but since they have a limited depth of penetration in tissues, higher energy (> .5ev < 10 kev) epithermal neutron beams, which have a greater depth of penetration, were used in clinical trials in the united states, europe, japan, argentina, taiwan, and china until recently when accelerators replaced the reactors. in theory bnct is a highly selective type of radiation therapy that can target tumor cells without causing radiation damage to the adjacent normal cells and tissues. doses up to 60–70 grays (gy) can be delivered to the tumor cells in one or two applications compared to 6–7 weeks for conventional fractionated external beam photon irradiation. however, the effectiveness of bnct is dependent upon a relatively homogeneous cellular distribution of 10b within the tumor, and more specifically within the constituent tumor cells, and this is still one of the main unsolved problems that have limited its success. radiobiological considerations the radiation doses to tumor and normal tissues in bnct are due to energy deposition from three types of directly ionizing radiation that differ in their linear energy transfer (let), which is the rate of energy loss along the path of an ionizing particle: 1. low-let gamma rays, resulting primarily from the capture of thermal neutrons by normal tissue hydrogen atoms ; 2. high-let protons, produced by the scattering of fast neutrons and from the capture of thermal neutrons by nitrogen atoms ; and 3. high-let, heavier charged alpha particles (stripped down helium nuclei) and lithium-7 ions, released as products of the thermal neutron capture and decay reactions with 10b . since both the tumor and surrounding normal tissues are present in the radiation field, even with an ideal epithermal neutron beam, there will be an unavoidable, non-specific background dose, consisting of both high- and low-let radiation. however, a higher concentration of 10b in the tumor will result in it getting a higher total dose than that of adjacent normal tissues, which is the basis for the therapeutic gain in bnct. the total radiation dose in gy delivered to any tissue can be expressed in photon-equivalent units as the sum of each of the high-let dose components multiplied by weighting factors (gyw), which depend on the increased radiobiological effectiveness of each of these components. clinical dosimetry biological weighting factors have been used in all of the more recent clinical trials in patients with high-grade gliomas, using boronophenylalanine (bpa) in combination with an epithermal neutron beam. the 10b(n,α)7li part of the radiation dose to the scalp has been based on the measured boron concentration in the blood at the time of bnct, assuming a blood: scalp boron concentration ratio of 1.5:1 and a compound biological effectiveness (cbe) factor for bpa in skin of 2.5. a relative biological effectiveness (rbe) or cbe factor of 3.2 has been used in all tissues for the high-let components of the beam, such as alpha particles. the rbe factor is used to compare the biologic effectiveness of different types of ionizing radiation. the high-let components include protons resulting from the capture reaction with normal tissue nitrogen, and recoil protons resulting from the collision of fast neutrons with hydrogen. it must be emphasized that the tissue distribution of the boron delivery agent in humans should be similar to that in the experimental animal model in order to use the experimentally derived values for estimation of the radiation doses for clinical radiations. for more detailed information relating to computational dosimetry and treatment planning, interested readers are referred to a comprehensive review on this subject. boron delivery agents the development of boron delivery agents for bnct began in the early 1960s and is an ongoing and difficult task. a number of boron-10 containing delivery agents have been synthesized for potential use in bnct. the most important requirements for a successful boron delivery agent are: low systemic toxicity and normal tissue uptake with high tumor uptake and concomitantly high tumor: to brain (t:br) and tumor: to blood (t:bl) concentration ratios (> 3–4:1); tumor concentrations in the range of ~20-50 µg 10b/g tumor; rapid clearance from blood and normal tissues and persistence in tumor during bnct. however, as of 2021 no single boron delivery agent fulfills all of these criteria. with the development of new chemical synthetic techniques and increased knowledge of the biological and biochemical requirements needed for an effective agent and their modes of delivery, a wide variety of new boron agents has emerged (see examples in table 1). however, only one of these compounds has ever been tested in large animals, and only boronophenylalanine (bpa) and sodium borocaptate (bsh), have been used clinically. table 1. examples of new low- and high-molecular-weight boron delivery agentsa,b boric acidboronated unnatural amino acids boron nitride nanotubesboronated vegf boron-containing immunoliposomes and liposomescarboranyl nucleosides boron-containing lipiodolcarboranyl porphyrazines boron-containing nanoparticlescarboranyl thymidine analogues boronated co-polymersdecaborone (gb10) boronated cyclic peptidesdodecaborate cluster lipids and cholesterol derivatives boronated dnac intercalatorsdodecahydro-closo-dodecaborate clusters boronated egf and anti-egfr moabslinear and cyclic peptides boronated polyaminespolyanionic polymers boronated porphyrinstransferrin-polyethylene glycol liposomes boronated sugars athe delivery agents are not listed in any order that indicates their potential usefulness for bnct. none of these agents have been evaluated in any animals larger than mice and rats, except for boronated porphyrin (bopp) that also has been evaluated in dogs. however, due to the severe toxicity of bopp in canines, no further studies were carried out. bsee barth, r.f., mi, p., and yang, w., boron delivery agents for neutron capture therapy of cancer, cancer communications, 38:35 (doi: 10.1186/s40880-018-0299-7), 2018 for an updated review. cthe abbreviations used in this table are defined as follows: bnct, boron neutron capture therapy; dna, deoxyribonucleic acid; egf, epidermal growth factor; egfr, epidermal growth factor receptor; moabs, monoclonal antibodies; vegf, vascular endothelial growth factor. the major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting in order to achieve boron concentrations (20-50 µg/g tumor) sufficient to produce therapeutic doses of radiation at the site of the tumor with minimal radiation delivered to normal tissues. the selective destruction of infliltrative tumor (glioma) cells in the presence of normal brain cells represents an even greater challenge compared to