title: Three-dimensional human arterial wall models for in vitro permeability assessment of drug and nanocarriers.
abstract: Monolayers of endothelial cells (1L-ECs) have been generally used as in vitro vascular wall models to study the vascular mechanisms and transport of substances. However, these two-dimensional (2D-) system cannot represent the properties of native vascular walls which have a 3D-structure and are composed of not only ECs, but also smooth muscle cells (SMCs) and other surrounding tissues. Here in, 5-layered (5L) 3D-arterial wall models (5L-AWMs) composed of EC monolayer and 4-layered SMCs were constructed by hierarchical cell manipulation. We applied the 5L-AWMs to evaluate their barrier function and permeability to nano-materials in order to analyze drug, or drug nanocarrier permeability to the blood vessel in vitro. Barrier property of the 3D-AWMs was confirmed by Zonula occludens (ZO-1) staining and their transendothelial electrical resistance (TEER), which was comparable to 1L-ECs, while the SMCs showed close to zero. The effect of substance size to permeability across the 5L-AWMs was clearly observed from dextrans with various molecular weights, which agreed well with the known phenomena of the in vivo blood vessels. Importantly, transport of nano-materials could be observed across the depth of 5L-AWMs, suggesting the advantage of 3D-AWMs over general 2D-systems. By using this system, we evaluate the transport of 35 nm phenylalanine-modified poly(γ-Glutamic Acid) nanoparticles (γ-PGA-Phe NPs) as a candidate of biodegradable drug carrier. Interestingly, despite of having comparable size to dextran-2000 k (28 nm), the γ-PGA-Phe NPs distinctly showed approximately 20 times faster transport across the 5L-AWMs, suggesting the effect of intrinsic properties of the substance on the transport. This in vitro evaluation system using the 3D-AWMs is therefore useful for the design and development of nano-drug carriers for treatment of vascular diseases, such as atherosclerosis.
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Paninee
authors.initials: P
authors.lastname: Chetprayoon
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Michiya
authors.initials: M
authors.lastname: Matsusaki
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Osaka, Japan. Electronic address: akashi@chem.eng.osaka-u.ac.jp.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Akashi
mesh_terms: D001158:Arteries / Q000473:pathology*; D001692:Biological Transport; D016207:Cytokines / Q000378:metabolism; D004337:Drug Carriers; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D017097:Electric Impedance; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008953:Models, Anatomic; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D010539:Permeability; D011099:Polyglutamic Acid / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D062826:Zonula Occludens-1 Protein / Q000737:chemistry
chemical_list: D016207:Cytokines; D004337:Drug Carriers; D011108:Polymers; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D011099:Polyglutamic Acid; D016650:Fluorescein-5-isothiocyanate
keywords: 3D-tissue; Arterial wall model; Dextran; Nanoparticles; Permeability assay; Poly(γ-Glutamic Acid)