Transepithelial Transport of PAMAM Dendrimers Across Isolated Human Intestinal Tissue

Poly­(amido amine) (PAMAM) dendrimers have shown transepithelial transport across intestinal epithelial barrier in rats and across Caco-2 cell monolayers. Caco-2 models innately lack mucous barriers, and rat isolated intestinal tissue has been shown to overestimate human permeability. This study is...

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Bibliographic Details
Published in:Molecular pharmaceutics 2015-11, Vol.12 (11), p.4099-4107
Main Authors: Hubbard, Dallin, Enda, Michael, Bond, Tanner, Moghaddam, Seyyed Pouya Hadipour, Conarton, Josh, Scaife, Courtney, Volckmann, Eric, Ghandehari, Hamidreza
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Animals
Biocompatible Materials - chemistry
Biocompatible Materials - pharmacokinetics
Biological Transport
Caco-2 Cells
Cell Membrane Permeability
Dendrimers - chemistry
Dendrimers - pharmacokinetics
Drug Delivery Systems
Female
Humans
Intestinal Mucosa - cytology
Intestinal Mucosa - metabolism
Male
Mannitol - metabolism
Middle Aged
Rats
Young Adult
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Summary:Poly­(amido amine) (PAMAM) dendrimers have shown transepithelial transport across intestinal epithelial barrier in rats and across Caco-2 cell monolayers. Caco-2 models innately lack mucous barriers, and rat isolated intestinal tissue has been shown to overestimate human permeability. This study is the first report of transport of PAMAM dendrimers across isolated human intestinal epithelium. It was observed that FITC labeled G4-NH2 and G3.5-COOH PAMAM dendrimers at 1 mM concentration do not have a statistically higher permeability compared to free FITC controls in isolated human jejunum and colonic tissues. Mannitol permeability was increased at 10 mM concentrations of G3.5-COOH and G4-NH2 dendrimers. Significant histological changes in human colonic and jejunal tissues were observed at G3.5-COOH and G4-NH2 concentrations of 10 mM implying that dose limiting toxicity may occur at similar concentrations in vivo. The permeability through human isolated intestinal tissue in this study was compared to previous rat and Caco-2 permeability data. This study implicates that PAMAM dendrimer oral drug delivery may be feasible, but it may be limited to highly potent drugs.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.5b00541