Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects

Abstract

Background: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer A particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. Boron Delivery Agents: Two boron drugs have been used clinically, sodium borocaptate (Na 2 B 12 H 11 SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations (f20 Ag/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boroncontaining amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. Clinical Trials: Current or recently completed clinical trials have been carried out inJapan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of ''debulking'' surgery to remove as much of the tumor as possible, followed by BNCTat varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established. Conclusions: Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCTcould move forward as a treatment modality.

Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head-and-Neck Cancer: Final Analysis of a Phase I/II Trial

“…We have, therefore, initiated a prospective clinical trial where cetuximab, a monoclonal antibody directed at the epidermal growth factor receptor, is given immediately after BNCT (ClinicalTrials.gov identifier NCT00927147). Other potential approaches that might improve the efficacy of BNCT include sequential administration of BNCT with intensity-modulated radiotherapy, concomitant administration of platinum compounds, intra-arterial or prolonged infusion of the boron carrier (27), and novel boron carrier compounds (9). BNCT warrants further study also among a patient population with unresectable head-and-neck cancer as first-line treatment, perhaps as administered before conventional chemoradiation therapy.…”

“…BNCT is based on the neutron capture reaction that occurs when nonradioactive boron ( 10 B) is irradiated with neutrons of low (thermal) energy. This causes a nuclear decay yielding high-energy a particles and recoiling lithium ( 7 Li) nuclei (9). Because a and 7 Li have short range in tissue and they produce dense ionization along their tracks, most radiation effect is local and occurs within the cells that contain boron.…”

Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy

“…The resonance-stabilized delocalization of the positive charge of DLCs, coupled with their inherent lipophilicity, leads to a decrease in the cost associated with the free energy change that accompanies the diffusion of DLCs through cell membranes, and provides the 5 driving force for their observed highly selective accumulation (>100 fold) in the mitochondrial matrix of cancer cells [13,17,18] and the associated high (>5 fold) difference between their cytoplasmic and extracellular concentrations [11]. Towards the development of highly selective target-specific anticancer agents that are applicable to boron neutron capture therapy (BNCT) of cancer, this study builds on preliminary evaluations that indicated the selective accumulation of boronated DLC compounds in cancer cells [19,20]. In particular, the experimental work focuses on the pharmacological evaluation at cellular and molecular level of four of these boron molecules, the molecular design of which combines the tumor-cell specificity of Moreover, molecular gene expression profiling has indicated that the DLC-carboranes exert their pharmacological properties through the activation of the p53/p21 axis, a crucial molecular pathway long known to control cell cycling and growth arrest.…”

Synthesis and in vitro properties of trimethylamine- and phosphonate-substituted carboranylporphyrins for application in BNCT

“…Dipyrromethanes 4 were prepared from the reaction of the corresponding benzaldehyde with an excess of pyrrole using TFA as the catalyst, in 70-86% yields, as previously reported. 25-27 The condensation of compounds 3 and 4a via a [2+2] methodology, 27-29 using BF 3 •OEt 2 for 1 h at room temperature, followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave porphyrins 6a, 7a and H 2 OCP in 2.1, 6.3 and 8.5% yields, respectively, as major products. On the other hand, the condensation of 3 and 4b under similar conditions but using BF 3 •OEt 2 for only 4 min, afforded porphyrins 6b, 7b, 8b and H 2 OCP in 2.6, 8.0, 4.5 and 2.1% yields, respectively.…”

“…25-27 The condensation of compounds 3 and 4a via a [2+2] methodology, 27-29 using BF 3 •OEt 2 for 1 h at room temperature, followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave porphyrins 6a, 7a and H 2 OCP in 2.1, 6.3 and 8.5% yields, respectively, as major products. On the other hand, the condensation of 3 and 4b under similar conditions but using BF 3 •OEt 2 for only 4 min, afforded porphyrins 6b, 7b, 8b and H 2 OCP in 2.6, 8.0, 4.5 and 2.1% yields, respectively. Other porphyrins were also obtained as minor products (< 1% yield) as a result of the scrambling but were not isolated in sufficient amounts for characterization.…”