A bifunctional carborane-quinazoline combines tumor growth inhibition and boron delivery for boron neutron capture therapy in melanoma and non-small cell lung cancer models

Background Boron neutron capture therapy (BNCT) is a binary therapeutic modality based on the nuclear reaction between boron-10 ( 10 B) and low-energy neutrons, generating high-linear-energy-transfer (LET) α-particles ( 4 He) and recoiling lithium-7 ( 7 Li) nuclei with a very short path length, thereby inducing highly localized tumor cell damage. However, the clinically available boron delivery agents, 10 B-boronophenylalanine ( BPA ) and sodium 10 B-borocaptate ( BSH ), remain limited by suboptimal tumor selectivity, cellular uptake, and boron retention. Objective This study aimed to (i) evaluate the intrinsic antitumor activity of Cmpd. 1 in cutaneous melanoma (CM) and non-small cell lung cancer (NSCLC) models; (ii) assess its ability to deliver boron and mediate BNCT effects in vitro ; and (iii) evaluate its antitumor activity and boron biodistribution in vivo . Methods Cmpd. 1 was investigated in CM and NSCLC models using complementary in vitro and in vivo approaches, including analysis of EGFR and LAT1 expression, cellular boron uptake, neutron autoradiography, BNCT-mediated cytotoxicity, cell death, tumor growth inhibition, and biodistribution. Results NCI-H125 cells exhibited higher EGFR and LAT1 transcript levels, which may contribute to their greater sensitivity to Cmpd. 1 and to the higher BPA uptake observed in this model. Despite being supplied at an approximately ninefold lower total boron concentration than BPA , Cmpd. 1 produced greater cellular boron accumulation after 24 h and substantially higher uptake when normalized to the amount of boron added to the culture medium. In vitro BNCT significantly reduced cell viability in both tumor models, with apoptosis contributing substantially to the response in NCI-H125 cells mainly for Cmpd. 1 . Repeated in vivo administration of Cmpd. 1 delayed tumor growth in CM and NSCLC xenografts without significant body-weight loss. In the NSCLC model, co-administration of Cmpd. 1 and BPA resulted in a tumor boron concentration of approximately 23 μg B/g tissue and a tumor-to-blood boron ratio of 6.3. Conclusion These findings identify Cmpd. 1 as a promising EGFR-targeted boron delivery agent that combines intrinsic antitumor activity with efficient boron delivery, supporting its further development as a bifunctional platform for BNCT.