Anionic PAMAM dendrimers rapidly cross adult rat intestine in vitro: A potential oral delivery system?

Purpose. To investigate systematically the effect of polyamidoamine (PAMAM) dendrimer size, charge, and concentration on uptake and transport across t he adult rat intestine in vitro using the everted rat intestinal sac system . Methods. Cationic PAMAM dendrimers (generations 3 and 4) and anionic PAMAM dendrimers (generations 2.5, 3.5, and 5.5) that were modified to include on average a single pendant amino group were radioiodinated using the Bolton and Hunter Reagent. I-125-Labelled dendrimers were incubated with everted s acs in vitro and the transfer of radioactivity into the tissue and serosal fluid was followed with time. Results. The serosal transfer rates seen for all anionic generations were e xtremely high with Endocytic Indices (EI) in the range 3.4-4.4 mu L/mg prot ein/h. The concentration-dependence of serosal transfer was linear over the dendrimer concentration range 10-100 mu g/mL. For I-125-labelled generatio n 5.5 the rate of tissue uptake was higher (EI = 2.48 +/- 0.51 mu L/mg prot ein/h) than seen for I-125-labelled generations 2.5 and 3.5 (0.6-0.7 mu L/m g protein/h) (p < 0.05). The I-125-labelled cationic PAMAM dendrimers (gene rations 3 and 4) displayed a tissue uptake (EI = 3.3-4.8 mu L/mg protein/h) which was higher (p < 0.05) than the rate of serosal transfer (EI = 2.3-2. 7 mu L/mg protein/h), probably due to nonspecific adsorption of cationic de ndrimer to the mucosal surface. Conclusions. As the anionic PAMAM dendrimers displayed serosal transfer rat es that were faster than observed for other synthetic and natural macromole cules (including tomato lectin) studied in the everted sac system, these in teresting nanoscale structures may have potential for further development a s oral drug delivery systems.