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

Authors

Sebastian Flieger, Loyola University ChicagoFollow
Mao Takagaki, Osaka UniversityFollow
Natsuko Kondo, Kyoto UniversityFollow
Marlon Lutz Jr., Loyola University Chicago
Yash Gupta, Mayo ClinicFollow
Hiroki Ueda, Kyoto University
Yoshinori Sakurai, Kyoto University
Graham Moran, Loyola University ChicagoFollow
Prakasha Kempaiah, Mayo ClinicFollow
Narayan Hosmane, Northern Illinois UniversityFollow
Minoru Suzuki, Kyoto University
Daniel P. Becker Ph.D., Loyola University ChicagoFollow

Document Type

Article

Publication Date

4-9-2023

Publication Title

International Journal of Molecular Sciences

Volume

24

Issue

8

Pages

1-24

Publisher Name

MDPI

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.

Comments

Author Posting © The Author(s), 2023. This article is posted here by permission of MDPI for personal use and redistribution. This article was published open access in International Journal of Molecular Sciences, VOL.24,ISS.8, (April 9, 2023), https://doi.org/10.3390/ijms24086973

Recommended Citation

Flieger, Sebastian; Takagaki, Mao; Kondo, Natsuko; Lutz Jr., Marlon; Gupta, Yash; Ueda, Hiroki; Sakurai, Yoshinori; Moran, Graham; Kempaiah, Prakasha; Hosmane, Narayan; Suzuki, Minoru; and Becker, Daniel P. Ph.D.. Carborane-Containing Hydroxamate MMP Ligands for the Treatment of Tumors Using Boron Neutron Capture Therapy (BNCT): Efficacy without Tumor Cell Entry. International Journal of Molecular Sciences, 24, 8: 1-24, 2023. Retrieved from Loyola eCommons, Chemistry: Faculty Publications and Other Works, http://dx.doi.org/10.3390/ijms24086973

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Copyright Statement

© The Author(s), 2023.