Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-10Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model

E. Roda, S. Nion, G. Bernocchi, T. Coccini

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6 Citations (Scopus)

Abstract

Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood- brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-10Boronophenyl)alanine, L-10BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-10BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-10BPA toxicity at 80 mg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-10BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39±0.01 × 10 -3cm min-1), corroborating the scarce probability that L-10BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds.

Original languageEnglish
Pages (from-to)34-44
Number of pages11
JournalBrain Research
Volume1583
Issue number1
DOIs
Publication statusPublished - 2014

Fingerprint

Boron Neutron Capture Therapy
Blood-Brain Barrier
Alanine
Permeability
Boron
Pharmaceutical Preparations
Brain Neoplasms
Cytoskeletal Proteins
Poisons
Vimentin
Head and Neck Neoplasms
Immunoblotting
Neuroglia
Endothelial Cells
Immunohistochemistry
Medicine
In Vitro Techniques
Safety
Brain

Keywords

  • Central nervous system
  • Head tumours
  • In vitro
  • Screening study

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology
  • Medicine(all)

Cite this

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title = "Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-10Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model",
abstract = "Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood- brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-10Boronophenyl)alanine, L-10BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-10BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-10BPA toxicity at 80 mg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-10BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39±0.01 × 10 -3cm min-1), corroborating the scarce probability that L-10BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds.",
keywords = "Central nervous system, Head tumours, In vitro, Screening study",
author = "E. Roda and S. Nion and G. Bernocchi and T. Coccini",
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T1 - Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-10Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model

AU - Roda, E.

AU - Nion, S.

AU - Bernocchi, G.

AU - Coccini, T.

PY - 2014

Y1 - 2014

N2 - Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood- brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-10Boronophenyl)alanine, L-10BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-10BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-10BPA toxicity at 80 mg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-10BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39±0.01 × 10 -3cm min-1), corroborating the scarce probability that L-10BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds.

AB - Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood- brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-10Boronophenyl)alanine, L-10BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-10BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-10BPA toxicity at 80 mg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-10BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39±0.01 × 10 -3cm min-1), corroborating the scarce probability that L-10BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds.

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