title: A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA.
authors.forename: Micah John
authors.initials: MJ
authors.lastname: Luderer
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Muz
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: de la Puente
authors.affiliation: Department of Energy, Environmental and Chemical Engineering, Washington University in St. Louis, St. Louis, Missouri, 63130, USA.
authors.forename: Sanmathi
authors.initials: S
authors.lastname: Chavalmane
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Kapoor
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA.
authors.forename: Raymundo
authors.initials: R
authors.lastname: Marcelo
authors.affiliation: Department of Energy, Environmental and Chemical Engineering, Washington University in St. Louis, St. Louis, Missouri, 63130, USA.
authors.forename: Pratim
authors.initials: P
authors.lastname: Biswas
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thotala
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA.
authors.forename: Buck
authors.initials: B
authors.lastname: Rogers
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, 4511 Forest Park Ave., Room 3103, St. Louis, Missouri, 63108, USA. aazab@radonc.wustl.edu.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000008:administration & dosage / Q000378:metabolism*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D001896:Boron Compounds; D009593:Nitroimidazoles
keywords: BNCT; boron neutron capture therapy; glioma; hypoxia; tumor targeting