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

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.
Source :
International Journal of Molecular Sciences. Apr2023, Vol. 24 Issue 8, p6973. 24p.
Publication Year :
2023

Abstract

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 1 (B1) and 2 (B2) were studied in vitro for BNCT activity. The boronated MMP ligands 1 and 2 showed high in vitro tumoricidal effects in an in vitro BNCT assay, exhibiting IC50 values for 1 and 2 of 2.04 × 10−2 mg/mL and 2.67 × 10−2 mg/mL, respectively. The relative killing effect of 1 to L-boronophenylalanine (BPA) is 0.82/0.27 = 3.0, and that of 2 is 0.82/0.32 = 2.6, whereas the relative killing effect of 4 is comparable to boronophenylalanine (BPA). The survival fraction of 1 and 2 in a pre-incubation boron concentration at 0.143 ppm 10B and 0.101 ppm 10B, respectively, were similar, and these results suggest that 1 and 2 are actively accumulated through attachment to the Squamous cell carcinoma (SCC)VII cells. Compounds 1 and 2 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
16616596
Volume :
24
Issue :
8
Database :
Academic Search Index
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
163434874
Full Text :
https://doi.org/10.3390/ijms24086973