Nuclear‐Targeted Boron‐Lapatinib Hybrid for Enhanced Boron Neutron Capture Therapy in Advanced Thyroid Carcinoma

To enhance the effectiveness of boron neutron capture therapy (BNCT) for advanced thyroid carcinoma (ATC), we evaluated two previously synthesized boron-enriched derivatives of Lapatinib incorporating high-boron clusters. Lapatinib, a tyrosine kinase inhibitor (TKI), is clinically used in targeted therapy against tumor proliferation and progression. The compounds consisted of Lapatinib-pharmacophore linked either to an ortho-carborane cluster (Cmpd-1) or to a metallacarborane cobalta-bis-dicarbollide (COSAN) anion (Cmpd-2). In vitro studies using the ATC 8505C anaplastic thyroid carcinoma cells showed significant cellular uptake of both compounds. Neutron autoradiography revealed that Cmpd-2 is located predominantly within the nucleus, suggesting that nuclear targeting may contribute to its enhanced therapeutic potential. Subsequent BNCT irradiation experiments at the Argentine nuclear reactor RA-3 demonstrated a marked reduction in cell survival, decreased Ki-67 expression, and increased apoptosis for BNCT-Cmpd-2 compared with BNCT using boronophenylalanine (BPA, a standard positive control), neutron-alone, and control groups. In vivo studies in ATC xenografted nude mice confirmed the absence of systemic toxicity and a significant inhibition of tumor growth following Cmpd-2 treatment (p < 0.01). Boron biodistribution analyses revealed favorable tumor-to-blood ratios (>3) when Cmpd-2 was combined with BPA. Overall, these results support Cmpd-2 as a promising bimodal agent for targeted and neutron-based therapy of advanced thyroid cancer.