title: Intracellular Ca2+ release mediates cationic but not anionic poly(amidoamine) (PAMAM) dendrimer-induced tight junction modulation.
abstract: OBJECTIVE
  Poly(amidoamine) (PAMAM) dendrimers show great promise for utilization as oral drug delivery vehicles. These polymers are capable of traversing epithelial barriers, and have been shown to translocate by both transcellular and paracellular routes. While many proof-of-concept studies have shown that PAMAM dendrimers improve intestinal transport, little information exists on the mechanisms of paracellular transport, specifically dendrimer-induced tight junction modulation.
  
  
  METHODS
  Using anionic G3.5 and cationic G4 PAMAM dendrimers with known absorption enhancers, we investigated tight junction modulation in Caco-2 monolayers by visualization and mannitol permeability and compared dendrimer-mediated tight junction modulation to that of established permeation enhancers. [(14)C]-Mannitol permeability in the presence and absence of phospholipase C-dependent signaling pathway inhibitors was also examined and indicated that this pathway may mediate dendrimer-induced changes in permeability.
  
  
  RESULTS
  Differences between G3.5 and G4 in tight junction protein staining and permeability with inhibitors were evident, suggesting divergent mechanisms were responsible for tight junction modulation. These dissimilarities are further intimated by the intracellular calcium release caused by G4 but not G3.5. Based on our results, it is apparent that the underlying mechanisms of dendrimer permeability are complex, and the complexities are likely a result of the density and sign of the surface charges of PAMAM dendrimers.
  
  
  CONCLUSIONS
  The results of this study will have implications on the future use of PAMAM dendrimers for oral drug delivery.
authors.affiliation: Department of Pharmaceutical Sciences Center for Nanomedicine and Cellular Drug Delivery, University of Maryland, Baltimore, 20 Penn Street, Health Sciences Facility II, Room 543, Baltimore, Maryland, 21201, USA.
authors.forename: Brittany R
authors.initials: BR
authors.lastname: Avaritt
authors.forename: Peter W
authors.initials: PW
authors.lastname: Swaan
mesh_terms: D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D050091:Dendrimers / Q000494:pharmacology*; D006801:Humans; D008353:Mannitol / Q000493:pharmacokinetics*; D018994:Myosin Light Chains / Q000378:metabolism; D009757:Nylons / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects*; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D050091:Dendrimers; D018994:Myosin Light Chains; D009757:Nylons; C104700:PAMAM Starburst; C520550:PAMAM-G4; D008353:Mannitol; D002118:Calcium