Highly soluble prodrug boronophenylalanine (L-BPA) dipeptide, exhibits notable tumor suppression whilst inducing cancer vaccine effect post neutron irradiation treatment

Boron Neutron Capture Therapy (BNCT) is an emerging cancer treatment modality that has seen a resurgence due to its efficacy and the advent of compact neutron beam devices. BNCT is a binary cancer treatment that combines selective boron delivery with epithermal neutron irradiation. When 10 B-enriched compounds accumulate in tumor cells and capture low-energy neutrons, the reaction generates high-linear energy transfer (LET) alpha-particles and 7 Li nuclei that deposit their energy within a few microns, producing irreparable DNA double-strand breaks and tumor cell death while sparing normal tissues. The clinical success of BNCT critically depends on the selective delivery of sufficient boron to tumors. Currently, 4- l-boronophenylalanine (l-BPA) is the leading BNCT agent, as it exploits LAT-1 (SLC7A5), a transporter highly expressed in many solid tumors. However, l-BPA suffers from poor solubility, severely limiting the maximum intravenous dose that can be administered and thereby constraining therapeutic efficacy. Here we report the synthesis and evaluation of highly soluble 10 B-enriched l-BPA-based dipeptides as next-generation boron delivery agents. These dipeptides, incorporating hydrophilic peptide linkages, enabled substantially higher intravenous bolus doses in mice compared to l-BPA while maintaining favorable biodistribution. In vivo, the dipeptides were rapidly cleaved by endogenous proteases, releasing l-BPA de novo within tumors. Neutron irradiation of syngeneic CT26 tumors in dipeptide-treated mice produced complete and durable tumor regressions, accompanied by immunological effects including a vaccine response and abscopal tumor suppression. By contrast, l-BPA administered at its solubility-limited maximal dose and using the same irradiation produced only transient growth delay without durable regression or immune activation. These findings establish dipeptides as a promising strategy to overcome the solubility limitations of l-BPA, enabling higher boron delivery, improved tumor control, and immune-mediated benefits. This approach could significantly expand the therapeutic potential of BNCT.