Neutron capture therapy of cancer
Neutron capture therapy 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, which has a high propensity to capture low-energy "thermal" neutrons. The neutron cross section of B 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 B atoms. The resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up enough B.
All clinical experience with NCT to date is with boron-10; hence, this method is known as boron neutron capture therapy. 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
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 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, 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, USA. Another clinical trial was initiated in 1954 by Sweet at the Massachusetts General Hospital using the MIT Nuclear Research Reactor 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 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, Taiwan, and Argentina. After the nuclear accident at Fukushima in 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.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. This undergoes radioactive decay to produce high-energy alpha particles and high-energy lithium-7 nuclei. The nuclear reaction is:
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, 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 thermal neutron beams were used in Japan and the United States, but since they have a limited depth of penetration in tissues, higher-energy 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 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, which is the rate of energy loss along the path of an ionizing particle:- Low-LET gamma rays, resulting primarily from the capture of thermal neutrons by normal tissue hydrogen atoms ;
- High-LET protons, produced by the scattering of fast neutrons and from the capture of thermal neutrons by nitrogen atoms ; and
- High-LET, heavier charged alpha particles and lithium-7 ions, released as products of the thermal neutron capture and decay reactions with B .
Clinical dosimetry
Biological weighting factors have been used in all of the more recent clinical trials in patients with high-grade gliomas, using boronophenylalanine in combination with an epithermal neutron beam. The BLi 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 factor for BPA in skin of 2.5. A relative biological effectiveness 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:brain and tumor:blood concentration ratios ;
- tumor concentrations in the range of ~20–50 μg B/g tumor;
- rapid clearance from blood and normal tissues and persistence in tumor during BNCT.
| Boric acid | Boronated unnatural amino acids |
| Boron nitride nanotubes | Boronated VEGF |
| Boron-containing immunoliposomes and liposomes | Carboranyl nucleosides |
| Boron-containing lipiodol | Carboranyl porphyrazines |
| Boron-containing nanoparticles | Carboranyl thymidine analogues |
| Boronated co-polymers | Decaborone |
| Boronated cyclic peptides | Dodecaborate cluster lipids and cholesterol derivatives |
| Boronated DNAc intercalators | Dodecahydro-closo-dodecaborate clusters |
| Boronated EGF and anti-EGFR MoAbs | Linear and cyclic peptides |
| Boronated polyamines | Polyanionic polymers |
| Boronated porphyrins | Transferrin-polyethylene glycol liposomes |
| Boronated sugars |
The 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 that also has been evaluated in dogs. However, due to the severe toxicity of BOPP in canines, no further studies were carried out.
See Barth, R.F., Mi, P., and Yang, W., Boron delivery agents for neutron capture therapy of cancer, Cancer Communications, 38:35 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 cells in the presence of normal brain cells represents an even greater challenge compared to malignancies at other sites in the body. Malignant gliomas are highly infiltrative of normal brain, histologically diverse, and heterogeneous in their genomic profile, and therefore it is very difficult to kill all of them.