Boron neutron capture therapy (BNCT) is a unique tumor cell targeting therapy (Soloway et al, Chem. Rev. 98:1515-1562, 1998; Barth et al., Clinical Res. 11:3987-4002, 2005). It is one of the binary cancer treatment systems that are based on the selective accumulation of boron-10 (10B) in tumors followed by irradiation with a neutron source. The selective accumulation of 10B in tumors and the subsequent capture of an epithermal neutron by a 10B atom, which produces an α-particle (He2+) and a lithium nucleus (7Li+) ejected in opposite directions within the tumor mass, make BNCT an attractive therapy for targeting tumors. The average track of these densely ionizing particles is approximately 14 μm, about the diameter of one cell, so that the killing of tumor cells is highly efficient (see Barth et al., Cancer 70:2995 3007, 1992; Barth et al., Neurosurg. 44:433 451, 1999; Soloway et al., J. Neurooncol. 33:9-18, 1997; and Soloway et al., 1998, supra). This promising radiation therapy requires the administration of tumor-seeking compounds containing 10B atoms that concentrate preferentially in tumor cells prior to irradiation with suitable low energy neutron beams. This binary modality is a highly attractive cancer therapy in that neither the thermal neutrons nor the boron carrier molecule has significant cytotoxic effect alone, but in combination they produce highly radiobiologically effective particles. The alpha particle and Li ion that are released as fission products when a thermal neutron is absorbed by a 10B atom have high linear energy transfer (LET) and a range similar to the dimensions of a mammalian cell. Thus, the absorbed dose, which is potent, is confined to cells adjacent to the boron atoms. The potential exists, therefore, to destroy tumor cells by radiosurgery at the microscopic level while sparing normal tissue in the vicinity of the tumor. BNCT is especially attractive for malignant brain tumors because it targets and destroys malignant cells but spares normal cells, thus preventing undesirable side effects common in standard chemo- or radiotherapy.
In recent years, several research groups have developed a variety of 10B carriers, including porphyrin derivatives with improved tumor selectivity over prior boron neutron capture agents, such as disodium mercapto-closo-dodecaborate (BSH) and L-4-dihydroxy-borylphenylalanine (BPA). Porphyrin derivatives are currently being tested in clinical trials in the U.S., Europe, and Japan for the treatment of patients with glioblastomas and melanomas (see, e.g., Bonnett et al., Chem. Soc. Rev. 24:19-33, 1995; Kageji et al., J. Neurooncol. 33:117-130, 1997; Pignol et al., Br. J. Radiol. 71:320-323, 1998; Elowitz et al., Neurosurgery 42:463-469, 1998). Although BSH and BPA have been shown to be safe and efficacious in animal models, several problems remain. For instance, BSH is sensitive to air-oxidation (Tolpin et al., Inorg. Chem. 17:2867-2873, 1978) and both BSH and BPA have low retention times in tissues and only moderate selectivity for tumor cells (Capala et al., Radiation Res. 146:554-560, 1996). At present, clinical progress is stalled due to the absence of effective boron delivery agents that target tumor cells with high selectivity. Obviously, the ultimate success of BNCT will be dependent upon whether adequate concentrations of boron neutron capture agents and low-energy neutrons can be selectively and effectively delivered to tumor cells.
Hypoxic tumor cells that comprise up to 50% of the mass of viable cells in human tumors pose a special impediment to effective radio- and chemotherapy. In particular, hypoxic cells are highly radio-resistant and capable of proliferation following radiation treatment. If boron containing therapeutics that interact with epithermal neutrons are not delivered to hypoxic sites in tumors it can be anticipated that the effectiveness of BCNT will be significantly compromised. In principal, BNCT is well suited to treating poorly oxygenated tumors since reduced radio-sensitivity in the absence of oxygen is less pronounced for high LET radiations, yet the effectiveness of BNCT therapy is dependent on delivery of the agent carrying the 10B atom to the tumor site.
2-nitroimidazoles readily penetrate tumors and can reach intratumor concentrations approaching 1 mM. As Varghese et al. showed in 1976 (Scobie et al., 1994), 2-nitroimidazoles also undergo nitroreductive activation under hypoxic conditions to yield electrophilic species that form adducts with cellular macromolecules, such as DNA and proteins. These adducts are retained in hypoxic cells and represent a useful targeting mechanism. In fact, carboranes have been linked to nitroimidazoles (Wood et al., 1996; Swenson et al., 1996) in attempts to target boron selectively to the hypoxic regions of tumors, but these boron delivery agents suffered greatly from poor water solubility. Thus, there remains a need for highly effective reagents for use in treating tumor tissue.