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 studie...

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Published in:International journal of molecular sciences 2023-04, Vol.24 (8), p.6973
Main Authors: Flieger, Sebastian, Takagaki, Mao, Kondo, Natsuko, Lutz, Jr, Marlon R, Gupta, Yash, Ueda, Hiroki, Sakurai, Yoshinori, Moran, Graham, Kempaiah, Prakasha, Hosmane, Narayan, Suzuki, Minoru, Becker, Daniel P
Format: Article
Language:English
Subjects:
BNCT
Boron Compounds - pharmacology
Boron Neutron Capture Therapy - methods
Boron-neutron capture therapy
cancer
carborane
Drug therapy
Enzymes
Glioma
Gliomas
Humans
Instrument industry
Ligands
matrix metalloproteinase
MMP
Squamous cell carcinoma
Virus Internalization
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms24086973