Anionic PAMAM Dendrimers Rapidly Cross Adult Rat Intestine In Vitro: A Potential Oral Delivery System?

AbstractPurpose. To investigate systematically the effect ofpolyamidoamine (PAMAM) dendrimer size, charge, and concentration on uptakeand transport across the adult rat intestine in vitro using theeverted 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 weremodified to include on average a single pendant amino group wereradioiodinated using the Bolton and Hunter Reagent. 125I-Labelleddendrimers were incubated with everted sacs in vitro and thetransfer of radioactivity into the tissue and serosal fluid was followedwith time. Results. The serosal transfer rates seen for all anionicgenerations were extremely high with Endocytic Indices (EI) in the range3.4–4.4 μmL/mg protein/h. The concentration-dependence of serosaltransfer was linear over the dendrimer concentration range 10–100μmg/mL. For 125I-labelled generation 5.5 the rate of tissueuptake was higher (EI = 2.48 ± 0.51 μmL/mg protein/h) thanseen for 125I-labelled generations 2.5 and 3.5 (0.6–0.7μmL/mg protein/h) (p < 0.05). The 125I-labelled cationicPAMAM dendrimers (generations 3 and 4) displayed a tissue uptake (EI= 3.3–4.8 μmL/mg protein/h) which was higher (p < 0.05)than the rate of serosal transfer (EI = 2.3–2.7 μmL/mgprotein/h), probably due to nonspecific adsorption of cationic dendrimer tothe mucosal surface. Conclusions. As the anionic PAMAM dendrimers displayedserosal transfer rates that were faster than observed for other syntheticand natural macromolecules (including tomato lectin) studied in the evertedsac system, these interesting nanoscale structures may have potential forfurther development as oral drug delivery systems.

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