Safety, efficacy, pharmacokinetics, and mechanisms of novel ¹⁰ B‐boronophenylalanine combined with a radio‐frequency quadrupole accelerator in boron neutron capture therapy: A preclinical study in head and neck squamous cell carcinoma

Background and Purpose Boron neutron capture therapy (BNCT) is an emerging binary‐targeted radiotherapeutic modality with promising potential for treating recurrent or refractory head and neck squamous cell carcinoma. We comprehensively evaluated the safety, efficacy, pharmacokinetics, and mechanisms of action of a novel 10 B‐boronophenylalanine ( 10 B‐BPA) combined with a radio‐frequency quadrupole (RFQ) accelerator‐based neutron source using systematic preclinical experiments. Methods This systematic preclinical study began by evaluating the drug's in vivo pharmacokinetics, tumor accumulation specificity, maximum tolerated dose, and systemic toxicity to verify its safety profile. Subsequently, its antitumor efficacy was assessed through dose‐dependent experiments, and the cellular and molecular mechanisms of BNCT treatment were investigated. Results The novel 10 B‐BPA exhibited rapid and highly specific tumor accumulation, achieving a stable tumor‐to‐blood ratio of approximately 3.5. The treatment resulted in dose‐dependent tumor regression without inducing systemic toxicity, with a maximum tolerated dose of more than 1000 mg/kg. Mechanistic investigations revealed that BNCT triggered a hypoxic stress response, leading to a substantial accumulation of reactive oxygen species and induced DNA double‐strand breaks. This metabolic crisis subsequently activated the hypoxia‐inducible factor‐1 alpha and nuclear factor kappa‐B signaling axes during apoptosis. Conclusions The novel 10 B‐BPA/RFQ accelerator‐based neutron source BNCT system demonstrates favorable safety, potent antitumor activity, and multi‐target molecular regulatory mechanisms. These findings provide a solid foundation for its clinical translation.