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Oral delivery remains a challengefor poorly permeable hydrophilicmacromolecules. Poly(amido amine) (PAMAM) dendrimers have shown potentialfor their possible oral delivery. Transepithelial transport of carboxyl-terminatedG3.5 and amine-terminated G4 PAMAM dendrimers was assessed using isolatedrat jejunal mucosae mounted in Ussing chambers. The 1 mM FITC-labeleddendrimers were added to the apical side of mucosae. Apparent permeabilitycoefficients (Papp) from the apical tothe basolateral side were significantly increased for FITC when conjugatedto G3.5 PAMAM dendrimer compared to FITC alone. Minimal signs of toxicitywere observed when mucosae were exposed to both dendrimers with respectto transepithelial electrical resistance changes, carbachol-inducedshort circuit current stimulation, and histological changes. [14C]-mannitol fluxes were not altered in the presence of 1mM dendrimers, suggesting that the paracellular pathway was not affectedat this concentration in this model. These results give insight intothe mechanism of PAMAM dendrimer transepithelial rat jejunal transport,as well as toxicological considerations important for oral drug delivery. [ABSTRACT FROM AUTHOR]

The influence of size, surface charge and surface functionality of poly(amido amine) dendrimers and silica nanoparticles (SNPs) on their toxicity was studied in immunocompetent mice. After systematic characterization of nanoparticles, they were administered to CD-1 (caesarean derived-1) mice to evaluate acute toxicity. A distinct trend in nanotoxicity based on surface charge and functional group was observed with dendrimers regardless of their size. Amine-terminated dendrimers were fatal at doses >10 mg/kg causing haematological complications such as disseminated intravascular coagulation-like manifestations whereas carboxyl- and hydroxyl-terminated dendrimers of similar sizes were tolerated at 50-fold higher doses. In contrast, larger SNPs were less tolerated than smaller SNPs irrespective of their surface functionality. These findings have important implications in the use of these nanoparticles for various biomedical applications. [ABSTRACT FROM AUTHOR]