Cellular evaluation of synthesized insulin/transferrin bioconjugates for oral insulin delivery using intelligent complexation hydrogels.

Insulin transport across the epithelial cell layer in the small intestine was studied using insulin/transferrin conjugates with and without the presence of P(MAA-g-EG) microparticles in contact with a co-culture of Caco-2/HT29-MTX cells. The insulin/transferrin conjugate was shown to increase transport relative to pure insulin by a factor of 7, achieving an apparent permeability of 37 x 10(9) cm . s(-1). The presence of P(MAA-g-EG) microparticles increased conjugate transport by a factor of 14 times relative to insulin, achieving an apparent permeability of 72.8 x 10(9) cm . s(-1). The presence of the microparticles in solution was found to improve conjugate transport by nearly 100% with little to no change in cell monolayer integrity.

[1]  N. Peppas,et al.  Investigation of the cytotoxicity and insulin transport of acrylic-based copolymer protein delivery systems in contact with Caco-2 cultures. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[2]  Per Artursson,et al.  Intestinal Drug Absorption and Metabolism in Cell Cultures: Caco-2 and Beyond , 1997, Pharmaceutical Research.

[3]  A. Fasano.  Novel approaches for oral delivery of macromolecules. , 1998, Journal of pharmaceutical sciences.

[4]  N. Peppas,et al.  Characterization of insulin protection properties of complexation hydrogels in gastric and intestinal enzyme fluids. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[5]  B. Gumbiner,et al.  Structure, biochemistry, and assembly of epithelial tight junctions. , 1987, The American journal of physiology.

[6]  N. Peppas,et al.  Design of poly(ethylene glycol)-tethered copolymers as novel mucoadhesive drug delivery systems. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[7]  W. Shen,et al.  Mechanisms of TfR-mediated transcytosis and sorting in epithelial cells and applications toward drug delivery. , 2003, Advanced drug delivery reviews.

[8]  G. Amidon,et al.  HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium: in vitro-in vivo correlation with permeability data from rats and humans. , 1996, Journal of pharmaceutical sciences.

[9]  K. Luthman,et al.  Caco-2 monolayers in experimental and theoretical predictions of drug transport , 1996 .

[10]  N. Peppas,et al.  Complexation graft copolymer networks: swelling properties, calcium binding and proteolytic enzyme inhibition. , 1999, Biomaterials.

[11]  Nicholas A Peppas,et al.  Mucosal insulin delivery systems based on complexation polymer hydrogels: effect of particle size on insulin enteral absorption. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[12]  J Carlsson,et al.  Protein thiolation and reversible protein-protein conjugation. N-Succinimidyl 3-(2-pyridyldithio)propionate, a new heterobifunctional reagent. , 1978, The Biochemical journal.

[13]  Lisbeth Illum,et al.  Effect of Chitosan on the Permeability of Monolayers of Intestinal Epithelial Cells (Caco-2) , 1994, Pharmaceutical Research.

[14]  S. Nigam,et al.  Molecular structure and assembly of the tight junction. , 1998, American journal of physiology. Renal physiology.

[15]  A. Ungell.  Caco-2 replace or refine? , 2004, Drug discovery today. Technologies.

[16]  G. Drewes,et al.  Probing the phalloidin binding site of actin , 1993, FEBS letters.

[17]  S. Chong,et al.  Cell culture-based models for intestinal permeability: a critique. , 2005, Drug discovery today.

[18]  Kristina Luthman,et al.  Caco-2 monolayers in experimental and theoretical predictions of drug transport1PII of original article: S0169-409X(96)00415-2. The article was originally published in Advanced Drug Delivery Reviews 22 (1996) 67–84.1 , 2001 .

[19]  N. Peppas,et al.  Novel complexation hydrogels for oral peptide delivery: in vitro evaluation of their cytocompatibility and insulin-transport enhancing effects using Caco-2 cell monolayers. , 2003, Journal of biomedical materials research. Part A.

[20]  N. Peppas,et al.  Hydrogels as mucoadhesive and bioadhesive materials: a review. , 1996, Biomaterials.

[21]  N. Peppas,et al.  Novel delivery system based on complexation hydrogels as delivery vehicles for insulin-transferrin conjugates. , 2006, Biomaterials.