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Thermal neutron

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478 keV

Figure 2.1 The mechanism of boron neutron capture therapy (BNCT) (see Plate 1)

the dissipated energy to the cell from which they arise, hence minimizing the effect on surrounding tissue. The capture cross section of boron for neutrons is more than three orders of magnitude higher than for other nuclei common in living tissue, so the target region can be dosed with neutrons at a sizeable flux and still have only minimal effect on boron-free regions in the beam path.17 Additional advantages of using 10B compared to other nuclides (e.g. 235U, 7Li) are that the fission products have high LET and the boron compounds can be synthesized having hydrolytically stable linkages between boron and elements such as C, O

and N.18

If boron can be transported to the target tissue with sufficient specificity and quantity using tumor-selective agents, tumor cell death may be accomplished. The required boron concentration is generally estimated at 109 atoms of 10B (natural abundance 19.9%) per cell, which translates to approximately 35 mg of 10B per gram of tissue. To prevent damage to healthy tissue in the path of the neutron beam, the surrounding tissue should contain no more than 5 mg of 10B per gram of tissue.19 A variety of carrier molecules have been investigated as boron delivery systems to tumor cells.19c,2° These include carbohydrates,21 poly-amines,22 nucleosides,23 antibodies,24 porphyrins,25 liposomes26 and amino acids.27 In order to obtain more favorable tumor to normal brain (T/N) and tumor to blood (T/B) ratios, and to significantly increase the amount of boron that can be incorporated into the tumor, a variety of structural modifications, using borane and carborane compounds, have been investigated.

Fast neutron therapy has long been used to treat cancer, including brain tumors.28 However, for certain brain tumors, e.g. glioblastoma multiforme, the prognosis is poor.29 After diagnosis, the expected survival time of 8 months can be extended by another 4 months by treatment using fast neutron therapy. There is essentially no difference in survival time between fast neutron and photon therapy for patients but the cause of death does depend upon the treatment. With fast neutron therapy, death results from significant damage to normal tissue. This is because of the close dose-effect relationship between tumor and healthy tissue. In photon therapy, regrowth of the tumor is the primary cause of death. A selective dose enhancement in tumor tissue using BNC (from the thermal and epithermal components of the fast neutron beam) would permit a reduction in overall dose thereby lowering the dose to normal tissue. Also, at depth, fast neutrons are therma-lized allowing capture by 10B, thus enhancing the applied dose. Even a relatively small percentage increase could have a significant clinical effect. The concentration of boron in tumors to bring about the BNC-enhanced fast neutron effect is thought to be 100 ppm. The application of current BNCT clinical trial agents, Na2B12H11SH (BSH) and p-boronophenylalanine (BPA) to assist in fast neutron therapy, is currently under consideration. However, such an application might not be practical because BSH, despite its high boron content, may actually have radio-protectant characteristics because of its thiol group.30

Several requirements must be met in order for this therapy to be effective: (i) a concentration of 25-30 mg of 10B atoms per gram of tumor must be achieved; (ii) a tumor to normal tissue (T:N) ratio of the boron delivery agent greater than 1 is necessary; (iii) the agent should be of low toxicity;19 and (iv) balance between the compound's lipophilic and hydrophilic components must be achieved. A series of compounds have been evaluated since the 1950s that include compounds containing one boron atom (aromatic boronic acids and related analogues) or many boron atoms (polyhedral borane anions, B10H102~ and B12H122~, and carborane cages, C2B10H10 and C2B9H10).19c

The primary focus of BNCT has been in the treatment of malignant brain tumors because these tumors have little history of metastasizing to other organ sites. Hence, if tumor eradication can be achieved in the brain, then there should be a significant increase in life expectancy. Only two compounds, BSH and BPA, are currently available for clinical trials.19c The results with these compounds are not promising; hence, there is an immediate need for potential precursor molecules and more sophisticated technologies that can selectively destroy tumor cells and lead to the expansion of BNCT. While the BSH is an anionic polyhedral borane icosahedron in which a thiol group replaces an exo-polyhedral hydrogen atom, the BPA is a boronophenylalanine. The structures of these two boron compounds are shown in Scheme 2.1.

Scheme 2.1 Boron compounds used in clinical trials, BSH (left) and BPA (right)

NH3+

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