Boron in my mind: A comprehensive review of the evolution and State-of-the-Art of the diverse syntheses of 4-borono-L-phenylalanine, the leading agent for boron neutron capture therapy

Boron Neutron Capture Therapy (BNCT) leverages the nuclear reaction between boron-10 and thermal neutrons to selectively destroy cancer cells while minimizing damage to surrounding healthy tissues. This therapy has found use in treating glioblastoma, which as a brain cancer, is difficult to treat using conventional radiotherapy, surgery, and chemotherapy due to location and the risk of brain damage. However, to work, the cells must contain 10B. 4-Borono-L-phenylalanine (L-BPA) is the most frequently used boron delivery agent in this therapy. The therapy is currently niche, requiring an available nuclear reactor to generate the high energy neutrons, and so demand for L-BPA is limited meaning that it is produced locally for clinical deployment. Surprisingly, despite its seemingly simple structure, there is no consensus approach to making it—the synthesis of L-BPA has been approached through multiple routes in both academic and patent literature, reflecting the challenges in producing high-purity, isotopically enriched material suitable for clinical use. When a new site is looking to make this essential material, it can be challenging to determine the best route for the situation as there is no critical analysis comparing and discussing the relative merits of the approaches. This comprehensive review, arising from our internal analysis to solve this same problem, is provided so that others will not need to replicate it. Herein, we critically examine and compare the reported methods, from both the academic and patent literature, used to synthesize L-BPA. We extend the analysis to comparing the different methods used to solubilize L-BPA. The review also highlights the limitations of each method regarding scalability, cost-effectiveness, and safety, especially considering the high cost of isotopically enriched 10B.