A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma
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Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation has been limited by the poor tumor selectivity of agents. To address this unmet need, a boronated 2-nitroimidazole derivative (B-381) was synthesized and evaluated for its capability of targeting hypoxic glioma cells.
B-381 has been synthesized from a 1-step reaction. Using D54 and U87 glioma cell lines, the in vitro cytotoxicity and cellular accumulation of B-381 has been evaluated under normoxic and hypoxic conditions compared to L-boronophenylalanine (BPA). Furthermore, tumor retention of B-381 was evaluated in vivo.
B-381 had low cytotoxicity in normal and cancer cells. Unlike BPA, B-381 illustrated preferential retention in hypoxic glioma cells compared to normoxic glioma cells and normal tissues in vitro. In vivo, B-381 illustrated significantly higher long-term tumor retention compared to BPA, with 9.5-fold and 6.5-fold higher boron levels at 24 and 48 h, respectively.
B-381 represents a new class of BNCT agents in which their selectivity to tumors is based on hypoxic tumor metabolism. Further studies are warranted to evaluate B-381 and similar compounds as preclinical candidates for future BNCT clinical trials for the treatment of glioma.
KEY WORDSBNCT boron neutron capture therapy glioma hypoxia tumor targeting
Proton nuclear magnetic resonance spectroscopy
Area under curve
Boron neutron capture therapy
Dulbecco’s modified eagle’s medium
Fetal bovine serum
High performance liquid chromatography
Inductively coupled plasma optical emission spectrometry
Mass to charge (m/z)
Peripheral blood mononuclear cells
Positron emission tomography
Parts per billion
ACKNOWLEDGMENTS AND DISCLOSURES
The first author thanks the N.I.H. Training Grant T32 GM007200 for research support. Mr. Luderer and Dr. Azab have a pending provisional patent application describing the work reported in this manuscript. Moreover, Dr. Azab receives research support from Verastem, Selexys, Karyopharm, Cell Works, Cleave Bioscience, and Glycomimetics; and is the founder and owner of Targeted Therapeutics LLC and Cellatrix LLC. Dr. de la Puente is co-founder of Cellatrix LLC. Other authors state no conflicts of interest.
- 2.Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-years analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66.CrossRefPubMedGoogle Scholar
- 5.Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma—are we there yet? Neuro-Oncology. 2012.Google Scholar
- 6.Azab AK, Abu Ali H, Srebnik M. Chapter 5 Boron neutron capture therapy. In: Hijazi Abu Ali VMD, Morris S, editors. Studies in Inorganic Chemistry: Elsevier; 2006. p. 337–66.Google Scholar
- 7.Luderer M, de la Puente P, Azab A. Advancements in tumor targeting strategies for boron neutron Capture Therapy. Pharm Res. 2015:1–13.Google Scholar
- 9.Chandra S, Barth RF, Haider SA, Yang W, Huo T, Shaikh AL, et al. Biodistribution and subcellular localization of an unnatural boron-containing amino acid (cis-ABCPC) by imaging secondary ion mass spectrometry for neutron capture therapy of melanomas and gliomas. PLoS ONE. 2013;8(9):e75377.CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Fu Y, Zheng S, Zheng Y, Huang R, An N, Liang A, et al. Glioma derived isocitrate dehydrogenase-2 mutations induced up-regulation of HIF-1alpha and beta-catenin signaling: possible impact on glioma cell metastasis and chemo-resistance. Int J Biochem Cell Biol. 2012;44(5):770–5.CrossRefPubMedGoogle Scholar
- 24.de la Puente P, Azab F, Muz B, Luderer M, Arbiser J, Azab AK. Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma. Leuk Lymphoma. 2015:1–10.Google Scholar
- 25.William T. Golde PG, Luis L. Rodriguez. A rapid, simple, and humane method for submandibular bleeding of mice using a lancet. Lab Animal. 2005;34(9):4.Google Scholar
- 28.Wittig A, Malago M, Collette L, Huiskamp R, Buhrmann S, Nievaart V, et al. Uptake of two 10B-compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC trial 11001). Int J Cancer. 2008;122(5):1164–71.CrossRefPubMedGoogle Scholar
- 35.Barth RF, Vicente MG, Harling OK, Kiger 3rd WS, Riley KJ, Binns PJ, et al. Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer. Radiat Oncol. 2012;7(146):7–146.Google Scholar
- 37.Hawthorne MF, Lee M. A critical assessment of boron target compounds for boron neutron capture therapy. J Neuro-Oncol. 2003;62(1–2):33–45.Google Scholar
- 39.Hosmane NS. Boron science: new technologies and applications. Boca Raton, FL: CRC Press; 2012.Google Scholar