Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, 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, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, the United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or “BPA”, and sodium borocaptate or “BSH” (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.

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Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer

This review focuses on the current status and perspectives of the application of polyhedral boron hydrides in medicine. The main topics discussed are boron neutron capture therapy for cancer and radionuclide diagnostics and therapy. X-ray contrast diagnostics, antitumor activity of some metal derivatives of carboranes, and drug design including carborane fragments are discussed as well.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Polyhedral Boranes for Medical Applications: Current Status and Perspectives

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.

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Boron delivery agents for neutron capture therapy of cancer

Cyclic oxonium derivatives of polyhedral boron hydrides are a relatively new class of boron compounds. They have great potential for the modification of various types of organic and bioorganic molecules and the synthesis of compounds that could be used in different fields from the treatment of nuclear wastes to the treatment of cancer. In the present Perspective we would like to present an overview of the results of the preparation and synthetic application of these compounds.

Cyclic oxonium derivatives of polyhedral boron hydrides and their synthetic applications

Metal boranes: Progress and applications

Conjugates of chlorin e6 with closo-dodecaborate and cobalt bis(dicarbollide) anions were synthesized for the first time in high yields using the advanced ‘click’ methodology. In vitro study on A549 human lung adenocarcinoma cells revealed that the synthesized boronated conjugates are able to penetrate and accumulate in cancer cells, but their intracellular concentration is not sufficient for effective photodynamic and boron neutron capture therapy of cancer. Copyright © 2009 John Wiley & Sons, Ltd.

Novel types of boronated chlorin e6 conjugates via ‘click chemistry’

New conjugates of cobalt bis(dicarbollide) with chlorophyll a derivatives

Synthesis of a cycloimide bacteriochlorin p conjugate with the closo-dodecaborate anion

Conjugates of boron clusters with derivatives of natural chlorin and bacteriochlorin

Boron neutron capture therapy (BNCT) is one of the new and promising methods for cancer treatment. 1—4 The further development of this method is inseparably associ� ated with the design of new boroncontaining drugs that can selectively accumulate in the tumor tissue. Amino ac� ids, peptides, nucleotides, and some other molecules trop� ic to tumors can be used as molecules performing the tar� geted boron transport to the tumor. The ability of porphy� rins to be accumulated in cancer cells is well known. This ability in combination with the photoinduced generation of reactive oxygen species makes it possible to use them as photosensitizers in anticancer photodynamic therapy (PDT). 5—7 Photosensitizers based on natural chlorophylls with the enhanced tropicity to tumors, low toxicity, and an intense absorption in the nearIR spectral region, provid� ing the laser radiation action on deeply localized layers of cancer tissues, are of special interest. Therefore, synthesis of conjugates of polyhedral boron compounds with natural porphyrins is a topical issue. 8—16 The porphyrin fragment in these compounds provides the transportation of the bo� roncontaining conjugate to cancer cells and a possibility of visualization of the tumor. The subsequent irradiation of the cells with thermal neutrons and their interaction with the 10 B isotope of boron compounds selectively accu� mulated in cancer cells should result in the selective de� struction of malignant neoplasms. In the present work, the Sonogashira reaction, which is actively employed in modern organic chemistry, 17,18 was used for the synthesis of boroncontaining conjugates of natural porphyrins.

Rustam A. Titeev

Papers

Novel types of boronated chlorin e6 conjugates via ‘click chemistry’

New conjugates of cobalt bis(dicarbollide) with chlorophyll a derivatives

Synthesis of a cycloimide bacteriochlorin p conjugate with the closo-dodecaborate anion

Conjugates of boron clusters with derivatives of natural chlorin and bacteriochlorin

Synthesis of cobalt bis(dicarbollide) conjugates with natural chlorins by the Sonogashira reaction