Regional Morphology and Transport of PAMAM Dendrimers Across Isolated Rat Intestinal Tissue.
Intestinal permeability of PAMAM dendrimers has been observed, giving rationale for their use in oral drug delivery as potential carriers of associated molecules. This study assessed the apparent permeability coefficients (Papp) of dendrimers across isolated rat intestinal regional mucosae, along with estimation of the maximum non-toxic concentration. Caco-2 monolayers were also used to assess the comparative Papp values between isolated mucosae and cell culture models. Concentrations from 0.1 to 10 mM of anionic and cationic dendrimers were tested in mucosae to assess their Papp, membrane TEER, [(14)C]-mannitol Papp, and histology. 0.1 mM concentrations of dendrimers were assessed over 120 min in Caco-2 cell monolayers as concentrations above that were cytotoxic. Jejunal transport of dendrimers was higher than transport in colonic epithelium. Monolayer Papp values of dendrimers were comparable to those of jejunal mucosae. Mucosae exposed to dendrimer concentrations of 10 mM for 120 min caused significant reduction in TEER and changes in tissue morphology; however, G3.5 was the only analogue that caused significant TEER reduction and morphological changes at 1 mM concentrations. Transport in jejunal mucosae appears to be the greatest indicating that the small intestinal will be the most likely region to target for oral drug delivery using PAMAM dendrimers.
Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, 36 S. Wasatch Dr., SMBB 5205, Salt Lake City, Utah, 84112, USA.|Department of Bioengineering, University of Utah, 36 S. Wasatch Blvd., Salt Lake City, Utah, 84112, USA.
Dallin
D
Hubbard
Department of Chemistry, Brigham Young University Idaho, Rexburg, Idaho, 83460, USA.
Tanner
T
Bond
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 36 S. Wasatch Dr., SMBB 5205, Salt Lake City, Utah, 84112, USA. hamid.ghandehari@pharm.utah.edu.|Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, 36 S. Wasatch Dr., SMBB 5205, Salt Lake City, Utah, 84112, USA. hamid.ghandehari@pharm.utah.edu.|Department of Bioengineering, University of Utah, 36 S. Wasatch Blvd., Salt Lake City, Utah, 84112, USA. hamid.ghandehari@pharm.utah.edu.
Hamidreza
H
Ghandehari
D000284:Administration, Oral; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D003106:Colon / Q000378:metabolism*; D050091:Dendrimers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism*; D008954:Models, Biological; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D050091:Dendrimers; C104700:PAMAM Starburst
dendrimers; epithelial transport; oral drug delivery; poly(amido amine) dendrimers