title: Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Different Surface Characteristics and Sizes in Excised Porcine Olfactory Epithelium.
abstract: The ability to deliver therapeutically relevant amounts of drugs directly from the nasal cavity to the central nervous system to treat neurological diseases is dependent on the availability of efficient drug delivery systems. Increased delivery and/or therapeutic effect has been shown for drugs encapsulated in nanoparticles; however, the factors governing the transport of the drugs and/or the nanoparticles from the nasal cavity to the brain are not clear. The present study evaluates the potential transport of nanoparticles across the olfactory epithelium in relation to nanoparticle characteristics. Model systems, 20, 100, and 200 nm fluorescent carboxylated polystyrene (PS) nanoparticles that were nonmodified or surface modified with polysorbate 80 (P80-PS) or chitosan (C-PS), were assessed for transport across excised porcine olfactory epithelium mounted in a vertical Franz diffusion cell. Assessment of the nanoparticle content in the donor chamber of the diffusion cell, accompanied by fluorescence microscopy of dismounted tissues, revealed a loss of nanoparticle content from the donor suspension and their association with the excised tissue, depending on the surface properties and particle size. Chitosan surface modification of PS nanoparticles resulted in the highest tissue association among the tested systems, with the associated nanoparticles primarily located in the mucus, whereas the polysorbate 80-modified nanoparticles showed some penetration into the epithelial cell layer. Assessment of the bioelectrical properties, metabolic activity, and histology of the excised olfactory epithelium showed that C-PS nanoparticles applied in pH 6.0 buffer produced a damaging effect on the epithelial cell layer in a size-dependent manner, with fine 20 nm sized nanoparticles causing substantial tissue damage relative to that with the 100 and 200 nm counterparts. Although histology showed that the olfactory tissue was affected by the application of citrate buffer that was augmented by addition of chitosan in solution, this was not reflected in the bioelectrical parameters and the metabolic activity of the tissue. Regarding transport across the excised olfactory tissue, none of the nanoparticle systems tested, irrespective of particle size or surface modification, was transported across the epithelium to appear in measurable amounts in the receiver chamber.
authors.affiliation: †Advanced Drug Delivery and Tissue Engineering Division, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, U.K.
authors.forename: Alpesh
authors.initials: A
authors.lastname: Mistry
authors.affiliation: †Advanced Drug Delivery and Tissue Engineering Division, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, U.K.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Stolnik
authors.affiliation: ‡IDentity, 19 Cavendish Crescent North, The Park, Nottingham NG7 1BA, U.K.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Illum
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D066298:In Vitro Techniques; D053758:Nanoparticles / Q000008:administration & dosage / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism*; D009831:Olfactory Mucosa / Q000378:metabolism*; D010316:Particle Size; D013499:Surface Properties; D013552:Swine
keywords: chitosan; excised tissue; nose-to-brain delivery; olfactory epithelium; polysorbate 80; transepithelial transport