Cellular Entry of G3.5 Poly (amido amine) Dendrimers by Clathrin- and Dynamin-Dependent Endocytosis Promotes Tight Junctional Opening in Intestinal Epithelia
Autor: | Deborah Sweet Goldberg, Hamidreza Ghandehari, Peter W. Swaan |
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Rok vydání: | 2010 |
Předmět: |
Dynamins
Dendrimers Pharmaceutical Science Context (language use) Endocytosis Clathrin Tight Junctions Dendrimer Humans Pharmacology (medical) Intestinal Mucosa Dynamin Pharmacology Microscopy Confocal biology Tight junction Chemistry Organic Chemistry Biological Transport Flow Cytometry Biochemistry biology.protein Biophysics Molecular Medicine Caco-2 Cells Drug carrier Intracellular Biotechnology |
Zdroj: | Pharmaceutical Research. 27:1547-1557 |
ISSN: | 1573-904X 0724-8741 |
Popis: | This study investigates the mechanisms of G3.5 poly (amido amine) dendrimer cellular uptake, intracellular trafficking, transepithelial transport and tight junction modulation in Caco-2 cells in the context of oral drug delivery.Chemical inhibitors blocking clathrin-, caveolin- and dynamin-dependent endocytosis pathways were used to investigate the mechanisms of dendrimer cellular uptake and transport across Caco-2 cells using flow cytometry and confocal microscopy.Dendrimer cellular uptake was found to be dynamin-dependent and was reduced by both clathrin and caveolin endocytosis inhibitors, while transepithelial transport was only dependent on dynamin- and clathrin-mediated endocytosis. Dendrimers were quickly trafficked to the lysosomes after 15 min of incubation and showed increased endosomal accumulation at later time points, suggesting saturation of this pathway. Dendrimers were unable to open tight junctions in cell monolayers treated with dynasore, a selective inhibitor of dynamin, confirming that dendrimer internalization promotes tight junction modulation.G3.5 PAMAM dendrimers take advantage of several receptor-mediated endocytosis pathways for cellular entry in Caco-2 cells. Dendrimer internalization by dynamin-dependent mechanisms promotes tight junction opening, suggesting that dendrimers act on intracellular cytoskeletal proteins to modulate tight junctions, thus catalyzing their own transport via the paracellular route. |
Databáze: | OpenAIRE |
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