Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery

Abstract Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate‐PEG‐PAMAM conjugates, with different degrees of substitution were synthesized by a two‐step reaction through a carbodiimide‐mediated coupling reaction and loaded with indomethacin. Folate‐PEG conjugation increased the drug loading efficiency by 10‐ to 20‐fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half‐life and mean residence time for the folate‐PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate‐PEG conjugates, thereby limiting gastric‐related side effect. The time‐averaged relative drug exposure (r_e) of the drug in paw for the folate‐PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T_e) was highest for folate‐PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate‐PEG‐PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side‐effects and higher targeting efficiency. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2007