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-(10)Boronophenyl)alanine, L-(10)BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-(10)BPA 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-(10)BPA toxicity at 80 µg 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-(10)BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39 ± 0.01 × 10(-3)cm min(-1)), corroborating the scarce probability that L-(10)BPA 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.
authors.affiliation: University of Pavia, Department of Clinical-Surgical, Diagnostic and Paediatric Sciences, Toxicology Unit, Pavia, Italy. Electronic address: elisa.roda@unipv.it.
authors.forename: E
authors.initials: E
authors.lastname: Roda
authors.affiliation: CELLIAL Technologies, Faculté Jean Perrin, Rue Jean Souvraz, Lens, France.
authors.forename: S
authors.initials: S
authors.lastname: Nion
authors.affiliation: University of Pavia, Department of Biology and Biotechnology "L. Spallanzani", Laboratory of Cellular Biology and Neurobiology, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bernocchi
authors.affiliation: Salvatore Maugeri Foundation IRCCS, Toxicology Division, Laboratory of Clinical Toxicology, Pavia, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Coccini
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001895:Boron / Q000493:pharmacokinetics / Q000633:toxicity; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002417:Cattle; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D062793:Occludin / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D010865:Pilot Projects; D051381:Rats; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology; D014746:Vimentin / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D001896:Boron Compounds; D062793:Occludin; D014746:Vimentin; D062826:Zonula Occludens-1 Protein; D010649:Phenylalanine; D001895:Boron; C033685:4-boronophenylalanine
keywords: Central nervous system; Head tumours; In vitro; Screening study