Boron neutron capture therapy of cancer: where do we stand now?

摘要

This is the third Editorial/Commentary that one of us (R. F. Barth) has written relating to boron neutron capture therapy (BNCT) [1, 2]. For those readers who are unfamiliar with BNCT we would refer them to several recent comprehensive reviews [3-5]. The second Editorial ended on a hopeful note that with the introduction of accelerator-based neutron sources (ABNSs), BNCT would enter into the mainstream of radiation therapy [2]. This indeed has happened most notably in Japan, where BNCT now is being used to treat patients with recurrent tumors of the head and neck region, high-grade gliomas, meningiomas and melanomas. Similarly, there has been great interest in China, as indicated by an impressive number of publications coming from both of them [4, 6, 7]. In contrast to the active programs in Asia, there has been no recent clinical activity relating to BNCT in the United States and Europe. Hopefully, however, after many delays, a clinical program will be initiated in the near future in Finland using an ABNS to treat patients with recurrent tumors of the head and neck region. The obvious question is why there hasn't been interest in BNCT by clinicians in the United States and Europe? In this Editorial, we will address this question and hopefully make a convincing case for the further development of BNCT as a cancer treatment modality. Why has it been so difficult to develop new boron delivery agents for BNCT? Very simply put, the requirements for such agents are very challenging [3, 5]. These include (1) delivery of ∼20-30 µg 10B/g tumor; (2) high (>1) tumor:normal tissue and tumor:blood boron concentration ratios during irradiation; and (3) rapid clearance of boron from normal tissues while persisting in the tumor during neutron irradiation. The intracellular localization of 10B in tumor cells is also important, and ideally, the closer to the nucleus, the better. To date, only two boron delivery agents have met many but not all of these requirements: a boron-containing derivative of phenylalanine, known as boronophenylalanine (BPA), and a polyhedral borane, known as sodium borocaptate (BSH). Finally, a major challenge in the development of effective boron delivery agents is their localization in all parts of the tumor and within all tumor cells. As reported by Elowitz et al. [8] and Goodman et al. [9], there was considerable variability in the boron concentrations of both BPA [8] and BSH [9] in multiple tissue samples taken from the same tumor. This would be especially true in brain tumors, since the blood-brain barrier limits trans-vascular entry of high-molecular weight boron delivery agents (>100 Da) into the tumor. Many classes of boron-containing delivery agents have been proposed, and these broadly can be divided into low-molecular weight agents, such as amino acids, peptides, polyamines, nucleosides, carbohydrates, and porphyrins, and high-molecular weight agents, such as liposomes, proteins, monoclonal antibodies, and nanoparticles [5, 10]. Between 2018 and 2023, many new boron delivery agents with different chemical characteristics have been reported in both the chemical [5] and biological literature [10]. Based on studies in mice, we believe that the most promising of these is the 3-isomer of BPA (3-BPA), which has 10-100 times greater solubility than that of the 4-isomer of BPA (4-BPA) which currently is being used clinically [3]. The tumor uptake of 3-BPA in B16F10 melanoma-bearing mice was equal to that of 4-BPA [11], which requires complexing with fructose or sucrose to increase its solubility. A second promising chemical modification of BPA has been described by Nomoto et al. [12], who have reported that poly(vinyl alcohol) (PVA) can form complexes with BPA, thereby producing reversible boronated esters. In vitro studies revealed that PVA-BPA attained 3.6 times higher intracellular boron concentrations than the fructose-BPA complex. In vivo studies were carried out with murine CT26 colon cancer cells, implanted s