Carborane-Containing Hydroxamate MMP Ligands for the Treatment of Tumors Using Boron Neutron Capture Therapy (BNCT): Efficacy without Tumor Cell Entry.

New carborane-bearing hydroxamate matrix metalloproteinase (MMP) ligands have been synthesized for boron neutron capture therapy (BNCT) with nanomolar potency against MMP-2, -9 and -13. New analogs are based on MMP inhibitor CGS-23023A, and two previously reported MMP ligands () and () were studied in vitro for BNCT activity. The boronated MMP ligands and showed high in vitro tumoricidal effects in an in vitro BNCT assay, exhibiting IC values for and of 2.04 × 10 mg/mL and 2.67 × 10 mg/mL, respectively. The relative killing effect of to L-boronophenylalanine (BPA) is 0.82/0.27 = 3.0, and that of is 0.82/0.32 = 2.6, whereas the relative killing effect of is comparable to boronophenylalanine (BPA). The survival fraction of and in a pre-incubation boron concentration at 0.143 ppm B and 0.101 ppm B, respectively, were similar, and these results suggest that and are actively accumulated through attachment to the Squamous cell carcinoma (SCC)VII cells. Compounds and very effectively killed glioma U87 delta EGFR cells after BNCT. This study is noteworthy in demonstrating BNCT efficacy through binding to MMP enzymes overexpressed at the surface of the tumor cell without tumor cell penetration.