Boron neutron capture therapy (BNCT) is a bimodal modality for cancer treatment consisting on the irradiation of 10B-rich tumors with low-energy (thermal) neutrons, with subsequent production of high linear energy transfer particles, 4He2+ (alpha-particle) and 7Li3+, which cause severe damage to tumor cells through ionization processes; see Barth, Soloway, Fairchild et al., infra; Barth, Soloway, Goodman et al., infra. Because the cytotoxic ions produced in the nuclear reaction have a limited distance of travel in tissue (approximately one cell diameter, 5–9 μm), the success of this modality for cancer therapy depends on the selective uptake of boron in the tumor cells; see Hawthorne, (1998), infra; Hawthorne, (1993). infra. Malignant brain tumors are responsible for more than 10,000 deaths per year in the United States, and BNCT is specially attractive as the treatment because it potentially targets and destroys malignant cells in the presence of normal cells, thus, preventing undesirable side effects common in other types of treatments. In addition, BNCT has advantages over photoradiation therapy in that neutron beams can penetrate upwards of ten times deeper, to reach deep-seated tumor sites (6–7 cm).
In recent years, several research groups have developed a variety of new 10B carriers with improved tumor selectivity over the two boron neutron capture agents currently undergoing clinical trials in the U.S., Europe, and Japan, for the treatment of patients with glioblastomas and melanomas disodium mercapto-closo-dodecaborate (BSH) and L-4-dihydroxy-borylphenylalanine (BPA). See Kageji, et al., infra. Pignol, et al., infra; Elowitz, et al., infra. To date, of all the new boron-delivery agents, porphyrins are particularly promising tumor-selective compounds because of their natural tendency to accumulate in neoplastic tissue; see Bonnett, infra. This property of porphyrins provides the basis for their use in another therapeutic method, the photodynamic therapy (PDT) of tumors; see Schnitmaker, et al., infra; Dougherty, et al., infra. PDT relies on the selective uptake of a photosensitizer in tumor tissues, followed by generation of singlet oxygen and other cytotoxic species upon irradiation with red light. Photofrin®, a porphyrin derivative and only FDA-approved PDT drug has been used to treat thousands of patients in Canada, Europe, Japan and U.S. with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract. In addition to necrosis as the result of oxidative damage, it has been recently shown that some porphyrins also induce apoptosis (programmed cell death), either upon irradiation with light (particularly at low light doses), or by accumulation of high drug levels in tissues, in the dark.; see Luo, Chang, et al., infra; Luo, Ke, et al., infra. The ability of porphyrin-PDT to induce apoptosis may also be an important element for the success of both PDT and BNCT modalities for cancer treatment. Photofrin® presents the disadvantages of being a complex mixture of compounds of variable composition. Thus, active research in the area of development of new and highly efficient PDT photosensitizers is underway. Also, boron-containing porphyrin derivatives that selectively localize in tumor cells have potential PDT applications; see Hill, Kahl, Stylli et al., infra.
Porphyrins and their diamagnetic metal complexes are highly fluorescent. This provides a means for detection of tumor cells and for investigation of the 10B localization in tumors and surrounding tissues; see Mang et al., infra.
Intracellular boron distribution and quantification play important roles in determining the dose and length of a neutron radiation period, as well as the success of BNCT treatment; see Nigg et al., infra. The intracellular localization of porphyrins is highly dependent upon their physicochemical properties, including structural features such as nature of peripheral side chains, hydrophobicity, charge, molecular weight, and amphiphilic character; see Woodburn, Vardaxis, et al., infra. Certain porphyrins have been reported to have the ability to target the nuclei of tumor cells and causing DNA damage through intercalation, or binding to DNA; see Munson and Fiel, infra; Schneider and Wang, infra; Ding et al., (1991), infra; Sari et al., infra; Penning et al., infra. Therefore, the newly developed BNCT agents will display an appropriate balance between hydrophobicity and hydrophilicity. This property will give adequate solubility in aqueous or biological media, and enhanced interaction with cell membranes.
Although BSH and BPA have been shown to be safe and efficacious in animal models, BSH is reported to be sensitive to air-oxidation (Tolpin et al., infra) and both BSH and BPA have only moderate selectivity for tumor cells and low retention times in tissues (Capala et al., infra). The ultimate success of BNCT is dependent upon whether adequate concentrations of boron-containing capture agents and low-energy neutrons can be selectively and effectively delivered to tumor cells. Since selective production of epithermal neutrons with high beam quality has been achieved by modern nuclear reactors (such as the one available at the McClellan Nuclear Radiation Center in Sacramento), the main unsolved problem in BNCT centers on the development of new effective 10B carriers, capable of selectively delivering substantial concentrations of 10B atoms to tumors. In the last ten years, several boron-containing porphyrin derivatives have been reported for application in BNCT and their in vitro and in vivo properties evaluated; see Hill, Kahl, Kaye et al., infra; Woodburn, Phadke et al., infra; Ceberg et al., infra; Ozawa et al., infra; Miura, Micca, et al., infra; Matsumura et al., infra. These studies reveal that boronated porphyrins accumulate within cells of glioma models to a much greater extent, and are retained for longer periods of time, than do BSH and BPA. In addition, along with low toxicities and favorable intracellular biodistributions, significantly higher tumor porphyrin ratios relative to blood and normal tissue are found for some of these boronated porphyrins. To date, amongst the porphyrin-based BNCT drugs reported, in vivo investigations with BOPP (a protoporphyrin-IX derivative) and NiTCP-H (a meso-tetraphenylporphyrin derivative) are the most promising; see Kahl and Koo, infra; Miura, Gabel et al., infra. BOPP contains four carboranyl residues linked by ester bonds to the porphyrin macrocycle. In vivo cleavage of such linkages has been accounted for the sometimes observed low retention times of this drug in tumor cells. The highly lipophilic NiTCP-H contains four ether-linked carboranyl moieties, and requires the use of solubilizing agents such as Cremophor EL (a polyethoxylated castor oil) and propylene glycol as delivery vehicles; secondary effects of these solubilizing agents are not yet well understood; see Woodcock et al., infra; Badary et al., infra. Other boron-containing porphyrins are reported in the literature, but they contain a lower percentage (5–15%) of boron by weight.
USPTO Backgrounds
USPTO Backgrounds