title: Quantitative evaluation of the effect of poly(amidoamine) dendrimers on the porosity of epithelial monolayers.
abstract: Poly(amidoamine) (PAMAM) dendrimers are a family of water-soluble polymers with a characteristic tree-like branching architecture and a large number of surface groups, which have been used to immobilize a variety of therapeutic molecules for targeted drug delivery. Earlier studies showed that small cationic PAMAM-NH2 and selected anionic PAMAM-COOH dendrimers permeate across in vitro models of the small intestinal epithelium by paracellular and transcellular transport mechanisms. The focus of this research is to mathematically calculate the effect of cationic, anionic, and neutral PAMAM dendrimers on the porosity of epithelial tight junctions as a function of dendrimers concentration, incubation time, generation number, and charge density. Results show that the increase in the concentration, incubation time and generation number of cationic G0-G2 PAMAM-NH2 and anionic G2.5 and G3.5 PAMAM-COOH dendrimers caused a corresponding increase in the porosity of Caco-2 cell monolayers. Neutral G2-G4 PAMAM-OH dendrimers had no effect on the porosity of intestinal cells. These results provide quantitative evidence that the observed increase in permeability of PAMAM dendrimers across Caco-2 cell monolayers is due to their effect on the organization of the tight junctions and the associated increase in membrane porosity. Furthermore, these results emphasize the potential of cationic PAMAM-NH2 and anionic PAMAM-COOH dendrimers to function as carriers for controlled oral drug delivery.
authors.affiliation: University of Michigan, Department of Biomedical Engineering, 1101 Beal Avenue, Lurie Biomedical Engineering Building, Room 2150, Ann Arbor, MI 48109-2099, USA.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Khalil
authors.initials: K
authors.lastname: Khanafer
authors.forename: Mohamed E H
authors.initials: ME
authors.lastname: El-Sayed
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D008353:Mannitol / Q000008:administration & dosage; D016062:Porosity
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D008353:Mannitol