title: PEGylated silicon nanowire coated silica microparticles for drug delivery across intestinal epithelium.
abstract: Composite particles made by growing nanoscopic silicon wires from the surface of monodispersed, microsized silica beads were tested in this study for their ability to affect the integrity and permeability of an epithelial cell layer. Polyethylene glycol (PEG) is known to sterically stabilize particles and prevent protein binding; as such, it is a routine way to impart in vivo longevity to drug carriers. The effect of the silica beads, both with and without silicon nanowires and PEG, on the disruption of the tight junctions in Caco-2 cells was evaluated by means of: (a) analysis of the localization of zonula occludens-1 (ZO-1), claudin-1 and f-actin; (b) measurements of trans-epithelial electrical resistance (TEER); (c) real-time quantitative RT-PCR analysis of the expression of PKC-α and PKC-z, which regulate the fluidity of cell membranes, and RhoA and Rac1, which are mainly involved in mechanotransduction processes; and (d) drug permeability experiments with fluorescein-sodium. The results have shown that Si-nanowire-coated silica microparticles added to Caco-2 cells in culture lead to alterations in tight junction permeability and the localization of ZO-1 and f-actin, as well as to decreased width of ZO-1 and claudin-1 at the tight junction and increased expression of PKC transcripts. Si-nanowire-coated silica microparticles increased the permeability of Caco-2 cell monolayers to fluorescein-sodium in proportion to their amount. Effects indicative of loosening the Caco-2 cell monolayers and increasing their permeability were less pronounced for PEGylated particles, owing to their greater supposed inertness in comparison with the non-functionalized beads and nanowires. The analyzed Si-nanowire-coated silica microparticles have thus been shown to affect membrane barrier integrity in vitro, suggesting the possibility of using nanostructured microparticles to enhance drug permeability through the intestinal epithelium in vivo.
authors: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158-2330, USA. vuk.uskokovic@ucsf.edu
authors: Vuk
authors: V
authors: Uskoković
authors: Phin Peng
authors: PP
authors: Lee
authors: Laura A
authors: LA
authors: Walsh
authors: Kathleen E
authors: KE
authors: Fischer
authors: Tejal A
authors: TA
authors: Desai
mesh_terms: D018938:Caco-2 Cells; D062445:Claudin-1; D016503:Drug Delivery Systems / Q000379:methods*; D019793:Fluorescein / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008863:Microspheres; D053770:Nanowires / Q000737:chemistry*; D010750:Phosphoproteins / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012825:Silicon / Q000737:chemistry*; D012822:Silicon Dioxide / Q000737:chemistry*; D062826:Zonula Occludens-1 Protein
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D011092:Polyethylene Glycols; D012822:Silicon Dioxide; D019793:Fluorescein; D012825:Silicon