State-of-the-art boron clusters for boron neutron-capture therapy

Boron neutron-capture therapy (BNCT) is a highly precise, cell-level cancer radiotherapy. It exploits the neutron-capture reaction that occurs when low-energy thermal neutrons are absorbed by a boron-10 atom, triggering a nuclear fission reaction that releases high-energy particles to selectively kill cancer cells. BNCT is at the forefront of cancer treatment. Presently, only sodium mercaptoundecahydro-closo-dodecaborate and boron borylphenylalanine (BPA) have been approved as boron drugs for clinical trials by the Food and Drug Administration. However, these drugs still suffer from shortcomings, such as poor targeting, low concentration in cancer cells, a short residence time, and low overall applicability. Conversely, boron clusters are three-dimensional polyhedral structures composed of carbon, boron, and hydrogen atoms. Owing to their excellent stability and unique three-dimensional shape, they are ideal candidates for next-generation boron drugs. These unique features make boron clusters an ideal model for correlating macroscopic properties with the microstructures of substances, providing a valuable framework for the rational design of next-generation boron drugs. Thus, from an interdisciplinary perspective, this review summarizes new strategies for constructing boron clusters, including multi-level structures. We describe key chemical strategies for their functionalization for clinical applications, reveal the multi-scenario applications of their line-functionalized derivatives, and highlight their cross-disciplinary value in precision synthesis, biomedicine, and advanced materials, all with a focus on elucidating the structure-function relationship in boron clusters. Additionally, we explored the latest advancements in the visual evaluation of BNCT, its anticancer mechanism, and exclusive neutron accelerator devices. In summary, the development of novel boron drugs based on functional boron clusters is a prerequisite to resolving the key technical issues in the research and development of new BNCT agents. This review provides insights into the design of new BNCT drugs, as well as related supporting equipment and treatment options, from the perspectives of medicinal chemistry and clinical applications.