| Autor: |
Patient JD; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom., Hajiali H; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom., Harris K; AstraZeneca, Macclesfield, United Kingdom., Abrahamsson B; AstraZeneca, Mölndal, Sweden., Tannergren C; AstraZeneca, Mölndal, Sweden., White LJ; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom., Ghaemmaghami AM; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom., Williams PM; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom., Roberts CJ; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom., Rose FRAJ; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. |
| Abstrakt: |
Advances in drug research not only depend on high throughput screening to evaluate large numbers of lead compounds but also on the development of in vitro models which can simulate human tissues in terms of drug permeability and functions. Potential failures, such as poor permeability or interaction with efflux drug transporters, can be identified in epithelial Caco-2 monolayer models and can impact a drug candidate's progression onto the next stages of the drug development process. Whilst monolayer models demonstrate reasonably good prediction of in vivo permeability for some compounds, more developed in vitro tools are needed to assess new entities that enable closer in vivo in vitro correlation. In this study, an in vitro model of the human intestinal epithelium was developed by utilizing nanofibers, fabricated using electrospinning, to mimic the structure of the basement membrane. We assessed Caco-2 cell response to these materials and investigated the physiological properties of these cells cultured on the fibrous supports, focusing on barrier integrity and drug-permeability properties. The obtained data illustrate that 2D Caco-2 Transwell ® cultures exhibit artificially high trans-epithelial electrical resistance (TEER) compared to cells cultured on the 3D nanofibrous scaffolds which show TEER values similar to ex vivo porcine tissue (also measured in this study). Furthermore, our results demonstrate that the 3D nanofibrous scaffolds influence the barrier integrity of the Caco-2 monolayer to confer drug-absorption properties that more closely mimic native gut tissue particularly for studying passive epithelial transport. We propose that this 3D model is a suitable in vitro model for investigating drug absorption and intestinal metabolism. |
