Scalable B–B Single-Bond Formation via Boron-Centered Carboranyl Radicals: Boryl-Carborane for Boron Neutron Capture Therapy Applications

Abstract For many decades, interest in the medical application of boron chemistry focuses mainly on the boron neutron capture therapy (BNCT) approach to cancer treatment, which is a transformative binary-targeted radiotherapeutic modality, yet its global clinical translation is limited by the lack of high-performance boron delivery agents. Icosahedral carboranes hold unparalleled potential for the development of BNCT agents due to their exceptional boron density, excellent metabolic stability, and unique 3D architecture, but their biomedical application is hampered by intrinsic superhydrophobicity, poor tumor targeting, and limited theragnostic modifiability. Herein, we report a class of boryl-carboranes as multifunctional boron-bearing building blocks that directly address these long-standing limitations. The pendant borane moiety is readily converted to B(OH)2 for tumor targeting and enhanced aqueous solubility, and to BF3K for 18F-PET theragnostic integration. To enable scalable synthesis, we develop the electron donor–acceptor (EDA) complex-based strategy for the controllable generation of boron-centered carboranyl radicals from N-hydroxyphthalimide (NHPI) carboranyl carboxyl esters. This additive-free, room-temperature photochemical strategy enables boron-centered carboranyl radical-mediated unsymmetrical B–B bond construction, with decagram-scale production achieved via a continuous-flow system. Mechanistic studies confirm the EDA complex-mediated radical pathway. In vitro and in vivo studies demonstrate that these boryl-carboranes exhibit excellent biosafety, favorable aqueous solubility, and better tumor boron uptake and accumulation than clinically established agents, rendering this platform potential for next-generation BNCT therapeutics.