Intestinal epithelial barrier

Kindon, H., Pothoulakis, C., Thim, L., Lynch-Devaney, K. and Podolsky, D.K. (1995) Trefoil peptide protection of intestinal epithelial barrier function cooperative interaction with mucin glycoprotein. Gastroenterobgy 109, 516-523. 

I. Williamson, R. Shah, M. MacKay, and P. Artursson. Transport and permeability properties of human Caco-2 cells an in vitro model of the intestinal epithelial barrier, J. Control. Release 1990, 33, 25-40... 

Magalhaes, J. G., Tattoli, I., and Girardin, S. E. 2007. The intestinal epithelial barrier How to distinguish between the microbial flora and pathogens. Semin Immunol 19 106-115. 

Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422 37-44 Daugherty AL, Mrsny RJ (1999) Transcellular uptake mechanisms of the intestinal epithelial barrier. Part one. PSTT 2 144-151... 

Madsen, K., Cornish, A., Soper, P., McKaigney, C., Jijon, H., Yachimec, C., Doyle, J., Jewell, L., and DeSimone, C. (2001). Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121(3), 580-591. 

Drugs can cross the intestinal epithelial barrier in a number of ways. They may permeate either through the cell (transcellular) or between adjacent cells (para-cellular). Enterocytes have tight intercellular junctions that restrict paracellular transport to small hydrophilic molecules.7 These cells possess active and facilita-tive transporters for nutrients, as well as an array of efflux transporters [e.g., P-glycoprotein (P-gp) and related transporters] and enzymes (e.g., cytochrome P450 type 3A4) that restrict transcellular absorption. Transcytotic transport of macromolecules is possible, but compounds are often destroyed in lysosomes. With the exception of M-cells, transcytosis is not considered a major mechanism of the transcellular pathway for absorption of macromolecules across gastrointestinal epithelium.6... 

Lencer, W.L, 2001. Microbes and microbial toxins paradigms for microbial-mucosal interactions V cholera invasion of the intestinal epithelial barrier by a stably folded protein toxin. Am. J. Physiol. Gastrointest. Liver Physiol., 280, pp. G781-G786. 

A. L. Daugherty and R. J. Mrsny, Transcellular uptake mechanisms of the intestinal epithelial barrier — Part one. Pharm. Sci. Technol. Today, 2(4), 144-151 (1999). 

Ohland, C.L. and Macnaughton, W.K. (2010). Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol 298, G807-819. 

Rowlands, B.J., and K.R. Gardiner, 1998. Nutritional modulation of gut inflammation. Proc Nutr Soc. 57, 395-401. Spreeuwenberg, M.A.M., J.M.A.J. Verdonk, H.R. Gaskins, and M.W.A. Verstegen, 2001. Small intestine epithelial barrier function is compromised in pigs with low feed intake at weaning. J. Nutr. 131, 1520-1527. 

Oral delivery is desirable due to the ease of administration, lower cost, and increased patient compliance. Despite these advantages, oral delivery of macromolecules is challenging due to low penetration across the intestinal epithelial barrier. To circumvent these barriers, drugs have been attached to mac-romolecular carriers such as dendrimers that can potentially aid in absorption across the intestinal epithelium. PAMAM dendrimers are effectively transported across epithelial barriers (Wiwattanapatapee et al. 2000 El-Sayed et al. 2002 Kitchens et al. 2006). SN-38, a potent anticancer drug, when complexed with PAMAM dendrimers showed increased solubility and uptake by Caco-2 cells (Kolhatkar et al. 2008). Orally administered anti-inflammatory drug ketoprofen in the form of PAMAM complexes (Man et al. 2006) prolonged activity and increased bio availability with a sustained release profile. 

The paracellular route is probably less significant in the transport of nanospheres as compared to the transcellular route Tlie tight junctions in between the cells may not allow nanospheres to cross the intestinal epithelial barrier via paracellular route. The transcellular route could allow a restricted passage of the nanospheres across the intestinal mucosal layer because of their moderate size range. In a tissue culture model using Caco-2 (enterocytes) cell monolayers, we have demonstrated transport of PLGA nanospheres across the cells. 

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