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., -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.
Dendritic Nanotechnologies, Inc., 2625 Denison Drive, Mount Pleasant, Michigan 48858, USA. chauhan@dnanotech.com
Abhay S
AS
Chauhan
Prakash V
PV
Diwan
Narenda K
NK
Jain
Donald A
DA
Tomalia
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002351:Carrageenan; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D006099:Granuloma / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013499:Surface Properties
D000893:Anti-Inflammatory Agents; D050091:Dendrimers; C531249:Poly(amidoamine); D011073:Polyamines; D002351:Carrageenan