Boron neutron capture enhancement of fast neutron therapy

#The present invention relates to the use of boron-containing agents in boron neutron capture therapy killing of target cells. More particularly, this invention relates to boron neutron capture enhancement of fast neutron radiation therapy.

#Shortly after the neutron was discovered by Chadwick in 1932, its potential use in the treatment of human malignancies was realized. The concept of nuclei having a characteristic effective cross-sectional area, expressed as units of 10.sup.-24 cm.sup.2 known as barn units, was introduced with this early work. The effective nuclear cross section of boron for neutron capture was known to be exceptionally large while borons neighbors in the periodic table, nitrogen and carbon, exhibited nuclear cross sections which were comparatively quite small.

#Taylor, Proc. Roy. Soc., A47: 873 (1935) described the capture of thermal neutrons by .sup.10 B nuclei followed by the production of .sup.4 He.sup.2+ (.alpha.-particles) and .sup.7 Li.sup.3+ with about 2 MeV of kinetic energy distributed between these two heavy ion products. It was also determined (Taylor, supra) that the translational range of the product ions was particularly short; about 7.6 .mu. in photographic gelatin and 1.1 cm in air. Consequently, the lithium ion and the .alpha.-particle products were short-range, energetic species capable of imparting immense local damage to organic materials through ionization processes.

#The foregoing aspects and other advantages of this invention will become more readily appreciated by reference to the following detailed description and accompanying drawings, wherein:

#FIG. 1 is a graphical representation of the percentage survival of V79 cells when subjected to fast neutron bombardment in vitro at 5 Gy in the presence of normal medium, normal medium plus 1.0 mM boric acid, or normal medium plus 1.0 mM BSH, as described in Example 1; and

#FIG. 2 is a graphical representation of the percentage survival of BL-6, B-16 tumor cells when subjected to fast neutron bombardment in vivo in BDF mice at 2.5 Gy after injection of 0.2 ml of normal saline, 100 mM boric acid, or 100 mM BSH, as described in Example 2.

#In accordance with the present invention, target cells are killed by irradiating the target cells, either in vitro or in vivo, with fast neutrons in the presence of a boron neutron capture agent comprising a plurality, and preferably at least nine, of .sup.10 B atoms per molecule of the agent. In other aspects of the present invention, tumor cells in a human or non-human animal are treated by administering to the human or non-human animal a boron neutron capture agent comprising at least nine .sup.10 B atoms per molecule of the agent in an amount effective to associate the boron neutron capture agent with the tumor cells, and then irradiating the tumor cells with fast neutrons.

#Suitable boron neutron capture agents useful in the practice of the invention include multiple .sup.10 B-atom containing compounds that specifically bind to the target cells, or are capable of being specifically targeted to the target cells using targeting vehicles well known to those skilled in the art. For example, the boron neutron capture agents may be based on polyhedral borane anion derivatives, such as closo-B.sub.12 H.sub.12.sup.2-- (Pitochelli, A. et al., J. Am. Chem. Soc. 82: 3228 et seq. (1960); Miller, H., J. Am. Chem. Soc. 85: 3885et seq. (1963)), or closo-B.sub.10 H.sub.10.sup.2-- (Hawthorne, M. F. et al., J. Am. Chem. Soc. 81: 5519 et seq. (1959); Lipscomb, A., J. Am. Chem. Soc. 81: 5833 et seq. (1959)). A representative, presently particularly preferred compound of this class includes BSH (B.sub.12 H.sub.12 SH.sup.2-- ; Knoth, W., J. Am. Chem. Soc. 86: 3973 et seq. (1964); Tolpin, E. et al., Inorg. Chem. 17: 2867 (1978)) that contains a thiol function to permit covalent disulfide bonds with thiol groups presented by serum and tumor proteins.

#Alternatively, the boron neutron capture agents of the invention may comprise two polyhedral borane anion cages linked together to form a linked cage structure comprising, for example 20 boron atoms (hereinafter referred to as "B20 compounds"; see M. F. Hawthorne, Angewandte Chemie, International Edition in English, 32: 950-984 (1993)). B.sub.20 compounds of the invention