A periodic development of BPA and BSH based derivatives in boron neutron capture therapy (BNCT)

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Abstract

A schematic representation of various judicious approaches for the synthesis of BPA and BSH modified compounds for effective BNCT.

Abstract

Boron neutron capture therapy (BNCT) is a particular type of radiotherapy that requires a selective and high concentration of boron accumulation in neoplastic cells. To distinguish the distribution of boron compounds between tumour and normal cells, multiple research groups have been involved and successively innovated a wide variety of boron-based compounds. Despite the development of numerous boron compounds, only boronophenylalanine (BPA) and sodium mercaptoundecahydro-closo-dodecaborate (BSH) have emerged as effective in clinical trials. Here, we highlight the detailed progress in the molecular design of BPA and BSH derivatives from the historical perspective to the latest advances in light of the widely accepted performance required for effective BNCT. In this report, we have provided an overview of a variety of derivatives of BPA and BSH, including amino acids, peptides, polymers, monoclonal antibodies and chelated complexes, and it is observed that such derivatives of BPA and BSH are judicious choices for BNCT. Finally, we have summarised the critical issues for BPA and BSH that must be addressed if BNCT is to become a more widely accepted clinical modality.

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Boron neutron capture therapy of cancer: current status and future prospects.

Carolina Vicente, Jeffrey A Coderre, Rolf Barth … (2005)

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 alpha 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. 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 ( approximately 20 microg/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 boron-containing 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. Current or recently completed clinical trials have been carried out in Japan, 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 BNCT at 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. 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 BNCT could move forward as a treatment modality.

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Iwona M. Codogni, Jonathan J. Wilson, A Barnum … (1998)

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A selective, cell-permeable optical probe for hydrogen peroxide in living cells.

Michelle C. Y. Chang, Arnd Pralle, Ehud Y. Isacoff … (2004)

We present the synthesis, properties, and biological applications of Peroxyfluor-1 (PF1), a new type of optical probe for intracellular imaging of hydrogen peroxide in living biological samples. PF1 utilizes a boronate deprotection mechanism to provide unprecedented selectivity and optical dynamic range for detecting H2O2 in aqueous solution over similar reactive oxygen species including superoxide, nitric oxide, tert-butyl hydroperoxide, and hydroxyl radical. We further demonstrate the value of this reagent for biological applications by imaging changes in [H2O2] in living mammalian cells.