Boron neutron capture therapy of cancer: Critical issues and future prospects

The role of radiotherapy in the management of cancer is well established. During the whole course of cancer treatment, more than 50% of all cancer patients need to undergo radiotherapy, which is always considered to be one curative treatment modality for localized cancers. However, radiotherapy may cause severe acute and late toxicities, especially in patients with recurrent cancer. With the development of physical and biological technology, some novel radiotherapeutic strategies have been developed which may address these issues.1 One of these is boron neutron capture therapy (BNCT), a targeted radiotherapy for cancer cells that preferentially accumulate drugs carrying the nonradioactive boron‐10 (10B). It is based on the nuclear capture and fission reactions that occur when 10B is irradiated with neutrons to yield linear energy transfer alpha particles (4He) and recoiling lithium‐7 (7Li) nuclei.2 The short range of this reaction limits the damage to only cancer cells without affecting normal cells, even if the two types of cells are mingled at the cancer margin. This property allows BNCT to be used to treat cancers without damaging the surrounding critical normal tissues.3 Indeed, BNCT has been clinically evaluated as an alternative to conventional radiotherapy for the treatment of multiple cancers, including high‐grade gliomas,4 primaries or cerebral metastases of melanoma,5 and head and neck cancer.6 However, if BNCT can be used clinically as a modality for the treatment of cancers, several critical issues regarding boron‐containing agents and their delivery strategies, neutron sources for BNCT and clinical studies of BNCT must be addressed. Here, we also provide several valuable clues that can be followed to solve these critical issues. Boron‐containing agents Conventional boron‐containing agent The ideal boron‐containing agent should fulfill the general requirements as follows: (i) low systemic toxicity; (ii) low normal tissue uptake with high tumor uptake (tumor/brain and tumor/blood boron ratios >3–4:1); (iii) tumor concentrations of approximately 20 μg 10B/g tumor; and (iv) persistence in tumor tissues but rapid clearance from normal tissues during BNCT. In the 1950s and early 1960s, the first‐generation boron‐containing agents, such as boric acid and some of its derivatives, were developed as delivery agents for BNCT. However, these chemical compounds are nonselective attaining low tumor/blood boron ratios and cannot achieve effective neutron capture therapeutic effects.7, 8 Therefore, the treatment of malignant tumors by BNCT using these agents has been proven to fail. In the 1960s, the clinical trials of BNCT used two second‐generation boron compounds. One of these was (L)‐4‐dihydroxy‐borylphenylalanine (BPA), which is based on aryl boronic acids. Another boron‐containing chemical is sulfhydrylboran (BSH), which is based on sodium mercaptoundecahydro‐closododecaborate. In comparison with the first‐generation boron‐containing agents, the second‐generation boron compounds have lower toxicity, higher tumor/blood boron ratios and persist longer in tumor xenografts. However, it should be noted that none fulfills the requirements for a successful boron delivery agent. The third‐generation boron‐containing agents mainly consist of a stable boron cluster attached through a hydrolytically stable linkage to a tumor‐targeting moiety, such as low or high molecular weight agents.9 Low molecular weight agents include boron‐containing amino acids, polyhedral boranes, biochemical precursors, DNA‐binding agents, glucose, mannose, ribose, gulose, fucose, galactose, maltose, lactose molecules, phosphates, phosphonates, phenylureas, thioureas, nitroimidazoles, amines, benzamides, isocyanates, nicotinamides, azulenes, and dequalinium derivatives. High molecular weight agents include monoclonal antibodies, receptor‐targeting agents, and liposomes, which have been shown to have better selective targeting properties compared to the first‐ and second‐generation boron compounds.2 However, the biological properties of these agents depend on the density of the targeted sites and very little biological data on the third‐generation boron‐containing agents have been reported to date.