Current Boron Agents: BPA and BSH
BPA:
In 1987, a Japanese dermatologist Dr. Mishima and his co-workers at Kobe University found that p-boronophenylalanine (BPA) is a suitable boron-delivery agent for BNCT to treat patients with cutaneous melanomas.
The structure of BPA highly resembles phenylalanine, a basic cell metabolite, which is often required by tumor cells at a much higher intake rate due to their rapid proliferative nature. BPA is believed to be transported by ATB0,+, LAT-1, and LAT transporters.
Although it contains multiple hydrogen-bonding elements, BPA is surprisingly difficult to dissolve in water. Later, it was found that fructose could form a stable complex with BPA that dramatically improves the solubility of BPA in water (about 100 g/l).4 Since then, BPA-fructose has emerged as one of the most commonly used formulations in the clinical studies of BNCT. To date, other polyols such as sorbitol or poly(vinyl alcohol) are used in complex with BPA.
BSH:
The first clinically used boron agent is sodium borocaptate (Na2B12H11SH, commonly known as BSH), whose structure is unique regular icosahedron of twelve boron atoms.
In 1967, Dr. Hatanaka and co-workers first reported the great potential of BSH as a boron agent for treatment of brain tumor. As early as next year, a team led by Hatanaka succeeded in treating patients with high grade glioma by administering BSH to them.
Although the pioneering work above suggested efficacy of BNCT, the success relied on the penetration of BSH to tumor through dysfunctional brain-blood barrier. In other words, BSH itself doesn’t actively accumulate into tumor. To achieve high accumulation of BSH to tumor tissues, a wide variety of boron carriers have been developed, such as BSH-containing distearoyl lipid liposomes (DSBL, Figure 2a),3 a block polymer PEG-b-P(Glu-SS-BSH) that forms polymeric micelles (Figure 2b).4 These nanomaterials can deliver high concentration of boron to tumor issues due to their enhanced permeability and retention (EPR) effect. Further developments to establish efficient boron delivery systems are still in high demand.
| BPA | BSH |
|---|---|
| Discovery: In 1967, Soloway and Hatanaka | Discovery: In 1967, Soloway and Hatanaka |
| First Use: In 1989, Mishima: Treatment of Melanoma | First Use: In 1989, Mishima: Treatment of Glioma |
| Chemical Characteristics: A Derivative of Tyrosine Selective Accumulation in Cancer Cells via LAT-1 (L-type Amino acid Transporter 1) | Chemical Characteristics: Boron cluster containing 12 boron atoms Non-Selective Accumulation in Cancer Cells |
References
BPA:
– R. L. Moss, Critical review, with an optimistic outlook, on Boron Neutron Capture Therapy (BNCT). Appl. Radiat. Isot. 88, 2–11 (2014)
– M. J. Luderer, P. de la Puente, A. K. Azab, Advancements in tumor targeting strategies for boron neutron capture therapy. Pharm. Res. 32, 2824–2836 (2015)
– T. Nomoto, N. Nishiyama, Design of drug delivery systems for physical energy-induced chemical surgery. Biomaterials 178, 583–596 (2018).
– Y. Mishima, C. Honda, M. Ichihashi, H. Obara, J. Hiratsuka, H. Fukuda, H. Karashima, T. Kobayashi, K. Kanda, K. Yoshino, Treatment of malignant-melanoma by single thermal-neutron capture therapy with melanoma-seeking 10B-compound. Lancet 2, 388–389 (1989).
– A. Wittig, W. A. Sauerwein, J. A. Coderre, Mechanisms of transport of p-borono- phenylalanine through the cell membrane in vitro. Radiat. Res. 153, 173–180 (2000).
– P. Wongthai, K. Hagiwara, Y. Miyoshi, P. Wiriyasermkul, L. Wei, R. Ohgaki, I. Kato,
– K. Hamase, S. Nagamori, Y. Kanai, Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB0,+, LAT1 and LAT2. Cancer Sci. 106, 279–286 (2015).
– Y. Mori, A. Suzuki, K. Yoshino, H. Kakihana, Complex-formation of p-boronophenylalanine with some monosaccharides. Pigment Cell Res. 2, 273–277 (1989).
BSH:
– Soloway, A. H.; Hatanaka, H.; Davis, M. A. J. Med. Chem. 1967, 10, 714-717.
– Hatanaka, H. J. Neurol. 1975, 209, 81-94.
– Koganei, H.; Ueno, M.; Tachikawa, S.; Tasaki, L.; Ban, H. S.; Suzuki, M.; Shiraishi, K.; Kawano, K.; Yokoyama, M.; Maitani, Y.; Ono, K.; Nakamura, H. Bioconjugate Chem. 2013, 24, 124-132.
– Mi, P.; Yanagie, H.; Dewi, N.; Yen, H. C.; Liu, X.; Suzuki, M.; Sakurai, Y.; Ono, K.; Takahashi, H.; Cabral, H.; Kataoka, K.; Nishiyama, N. J. Control. Release, 2017, 254, 1-9.–