Pharmaceutical Research

, Volume 33, Issue 10, pp 2530–2539 | Cite as

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma

  • Micah John Luderer
  • Barbara Muz
  • Pilar de la Puente
  • Sanmathi Chavalmane
  • Vaishali Kapoor
  • Raymundo Marcelo
  • Pratim Biswas
  • Dinesh Thotala
  • Buck Rogers
  • Abdel Kareem Azab
Research Paper



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.


BNCT boron neutron capture therapy glioma hypoxia tumor targeting 





Proton nuclear magnetic resonance spectroscopy


Area under curve


Boron neutron capture therapy




Sodium borocaptate


Dulbecco’s modified eagle’s medium


Fetal bovine serum


Glioblastoma multiforme


High performance liquid chromatography




Inductively coupled plasma optical emission spectrometry


Mass to charge (m/z)


Peripheral blood mononuclear cells


Phosphate-buffered saline


Positron emission tomography


Parts per billion


Tumor/normal tissue




Radiation therapy



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.

Supplementary material

11095_2016_1977_MOESM1_ESM.pptx (35 kb)
Supplementary Figure 1 (PPTX 34 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Micah John Luderer
    • 1
  • Barbara Muz
    • 1
  • Pilar de la Puente
    • 1
  • Sanmathi Chavalmane
    • 2
  • Vaishali Kapoor
    • 1
  • Raymundo Marcelo
    • 1
  • Pratim Biswas
    • 2
  • Dinesh Thotala
    • 1
  • Buck Rogers
    • 1
  • Abdel Kareem Azab
    • 1
  1. 1.Department of Radiation Oncology, Cancer Biology DivisionWashington University in St. Louis School of MedicineSt. LouisUSA
  2. 2.Department of Energy, Environmental and Chemical EngineeringWashington University in St. LouisSt. LouisUSA

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