title: Permeability of PEGylated immunoarsonoliposomes through in vitro blood brain barrier-medulloblastoma co-culture models for brain tumor therapy.
abstract: OBJECTIVE
  Owing to restricted access of pharmacological agents into the brain due to blood brain barrier (BBB) there is a need: 1. to develop a more representative 3-D-co-culture model of tumor-BBB interaction to investigate drug and nanoparticle transport into the brain for diagnostic and therapeutic evaluation. 2. to address the lack of new alternative methods to animal testing according to replacement-reduction-refinement principles. In this work, in vitro BBB-medulloblastoma 3-D-co-culture models were established using immortalized human primary brain endothelial cells (hCMEC/D3).
  
  
  METHODS
  hCMEC/D3 cells were cultured in presence and in absence of two human medulloblastoma cell lines on Transwell membranes. In vitro models were characterized for BBB formation, zonula occludens-1 expression and permeability to dextran. Transferrin receptors (Tfr) expressed on hCMEC/D3 were exploited to facilitate arsonoliposome (ARL) permeability through the BBB to the tumor by covalently attaching an antibody specific to human Tfr. The effect of anticancer ARLs on hCMEC/D3 was assessed.
  
  
  RESULTS
  In vitro BBB and BBB-tumor co-culture models were established successfully. BBB permeability was affected by the presence of tumor aggregates as suggested by increased permeability of ARLs. There was a 6-fold and 8-fold increase in anti-Tfr-ARL uptake into VC312R and BBB-DAOY co-culture models, respectively, compared to plain ARLs.
  
  
  CONCLUSIONS
  The three-dimensional models might be appropriate models to study the transport of various drugs and nanocarriers (liposomes and immunoarsonoliposomes) through the healthy and diseased BBB. The immunoarsonoliposomes can be potentially used as anticancer agents due to good tolerance of the in vitro BBB model to their toxic effect.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
authors.forename: Abdulghani
authors.initials: A
authors.lastname: Al-Shehri
authors.forename: Marco E
authors.initials: ME
authors.lastname: Favretto
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Ioannou
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Babette Barbash
authors.initials: BB
authors.lastname: Weksler
authors.forename: Terry L
authors.initials: TL
authors.lastname: Parker
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Kallinteri
mesh_terms: D000906:Antibodies / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002626:Chemistry, Pharmaceutical; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008081:Liposomes; D008527:Medulloblastoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry*; D011990:Receptors, Transferrin / Q000276:immunology / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D001152:Arsenicals; D018796:Immunoconjugates; D008081:Liposomes; D011990:Receptors, Transferrin; D011092:Polyethylene Glycols