Unexpected In Vivo Anti-Inflammatory Activity Observed for Simple, Surface Functionalized Poly(amidoamine) Dendrimers

We report unexpected anti-inflammatory properties for naked, unmodified poly(amidoamine) (PAMAM) dendrimers bearing simple surface functionality (e.g., -NH2, -OH, etc.). This property was discovered serendipitously while studying the drug delivery features of PAMAM dendrimer−indomethacin complexes. Activity was quantitated by using three independently recognized in vivo anti-inflammatory assay methods, namely, (1) the carrageenan-induced paw edema model (acute activity), (2) the cotton pellet test, and (3) the adjuvant-induced arthritis assay in rats (chronic activities). Those dendrimers bearing amine or hydroxyl surface groups exhibited significant anti-inflammatory activity in the carrageenan-induced paw edema model. For example, [core: 1,2-diaminoethane]; (G = 4.0); {dendri-poly(amidoamine)-(NH2)64} (i.e., G4-NH 2 ) exhibited a mean percent inhibition of 35.50 ± 1.6% 3 h after administration and [core: 1,2-diaminoethane] (G = 4.0); {dendri-poly(amidoamine)-(OH)64} (i.e., G4-OH) gave a mean percent inhibition of 31.22 ± 1.58% 3 h after administration. On the other hand, [core: 1,2-diaminoethane] (G = 4.5); {dendri-poly(amidoamine)-(CO2H)128} (i.e., G4.5-CO 2 H) exhibited mild anti-inflammatory activity with a mean percent inhibition of 14.00 ± 2.5% 3 h after administration. Unexpectedly, G4-NH 2 showed significantly higher activity compared to naked indomethacin (i.e., 50 ± 3.1% vs 22 ± 1.2%) using the cotton pellet granuloma model. Similarly, in the adjuvant-induced arthritis model, G4-NH 2 compared to naked indomethacin gave a mean percent inhibition of 30 ± 1.9% versus 11 ± 0.9% 14 days after administration.