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

Abstract

We report unexpected anti-inflammatory properties for naked, unmodified poly(amidoamine) (PAMAM) dendrimers bearing simple surface functionality (e.g., -NH(2), -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)-(NH(2))(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)-(CO(2)H)(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.

Dendrimers as anti-inflammatory agents

“…In this section, we summarize not only the antiinflammatory role of dendrimers displayed towards immune cells derived from myeloid lineage (such as monocyte-derived macrophages (MDMs), and immature dendritic cells) (Shaunak et al, 2004), peripheral blood monocytes (Fruchon et al, 2009) and peritoneal macrophages (Chauhan et al, 2009), but also towards the extravasation of inflammatory effectors (leukocytes) at the site of inflammation (Ulbrich et al, 2003), anti-HIV activity, anti-arthritis effect and inhibition of iNOS and COX-2 enzymes etc.…”

“…In a recent study, PAMAM dendrimers with terminal-NH 2 (G4-NH 2 ), -OH (G4-OH) and -COOH (G4.5-CO 2 H) (Chauhan et al, 2009) were used for the in vitro analysis of LPS-induced nitric oxide (NO) and cyclo-oxygenase 2 (COX-2) activity in rat peritoneal macrophages. G4-NH 2 and G4-OH dendrimers showed maximum inhibitory activity as compared to G4.5-CO 2 H. In another study, the aminoethylethanolamine-capped dendrimers (G4-AEEA) and hydroxyl terminated dendrimers (G4-OH) displayed highest inhibitory activity of COX-2.…”

“…Recently, Tomalia and his group suggested that dendrimers themselves can exhibit anti-inflammatory properties mainly through inhibiting COX-2 activity (Chauhan et al, 2009). Kakkar's group recently showed that dendrimers synthesized using alkyne-azide "click" chemistry act as antiinflammatory agents (Castonguay et al, 2011;Hourani, Kakkar et al, 2010;Sharma et al, 2011a,b).…”

“Click” Dendrimers as Anti-inflammatory Agents: With Insights into Their Binding from Molecular Modeling Studies

“…10−12 Surprisingly, PAMAM dendrimers without any drug payload have also been shown to exhibit antiinflammatory properties, particularly generation 4 (G4) PAMAM dendrimers. 12 It was suggested that the inhibition of COX-2 activity may explain some of the anti-inflammatory effects, although the specific mechanism(s) of G4 PAMAM action remain unclear. 12 In addition, G3 dendritic polyglycerol sulfates (dPGS) also possess anti-inflammatory properties, though through a completely different mechanism of action.…”

“…12 It was suggested that the inhibition of COX-2 activity may explain some of the anti-inflammatory effects, although the specific mechanism(s) of G4 PAMAM action remain unclear. 12 In addition, G3 dendritic polyglycerol sulfates (dPGS) also possess anti-inflammatory properties, though through a completely different mechanism of action. 13 It is believed that dPGS dendrimers may function as macromolecular inhibitors, through direct interactions with complement factors, essential mediators of the innate immune response.…”