Permeability of PEGylated Immunoarsonoliposomes Through In Vitro Blood Brain Barrier-Medulloblastoma Co-culture Models for Brain Tumor Therapy

• Published in: Pharmaceutical research Vol. 32; no. 3; pp. 1072 - 1083
• Main Authors: Al-Shehri, Abdulghani, Favretto, Marco E., Ioannou, Panayiotis V., Romero, Ignacio A., Couraud, Pierre-Olivier, Weksler, Babette Barbash, Parker, Terry L., Kallinteri, Paraskevi
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.03.2015; Springer Nature B.V
• Subjects: Antibodies - chemistry; Antibodies - metabolism; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Arsenicals - chemistry; Arsenicals - metabolism; Arsenicals - pharmacology; Biochemistry; Biological Transport; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - immunology; Blood-Brain Barrier - metabolism; Brain cancer; Capillary Permeability; Cell Line, Tumor; Cell Survival - drug effects; Cerebellar Neoplasms - immunology; Cerebellar Neoplasms - metabolism; Cerebellar Neoplasms - pathology; Chemistry, Pharmaceutical; Coculture Techniques; Endothelial Cells - drug effects; Endothelial Cells - immunology; Endothelial Cells - metabolism; Humans; Immunoconjugates - chemistry; Immunoconjugates - metabolism; Immunoconjugates - pharmacology; Liposomes; Medical Law; Medulloblastoma - immunology; Medulloblastoma - metabolism; Medulloblastoma - pathology; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Polyethylene Glycols - chemistry; Receptors, Transferrin - immunology; Receptors, Transferrin - metabolism; Research Paper; Technology, Pharmaceutical - methods; cell aggregates; hCMEC/D3 cells; blood brain barrier cancer model; arsonolipids; transferrin receptors
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-014-1519-8

ABSTRACT Purpose 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. Conclusion 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.