Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate–containing RGD peptide liposomes inhibits experimental arthritis

Objective To investigate whether RGD peptide–exposing long circulating polyethylene glycol (PEG) liposomes (RGD‐PEG–L) targeted to αvβ3 integrins expressed on angiogenic vascular endothelial cells (VECs) are able to bind VECs at sites of inflammation and whether such liposomes containing dexamethasone phosphate (DEXP) can be used as carriers to interfere with the development of experimental arthritis. Methods Binding and internalization of RGD‐PEG–L were studied by fluorescence‐activated cell sorting and confocal microscopy using fluorescently labeled liposomes. Radiolabeled liposomes were used to test in vivo pharmacokinetics and inflammation site targeting in lipopolysaccharide (LPS)–induced inflammation and adjuvant‐induced arthritis (AIA) in rats. In vivo inflammation targeting was visualized by intravital microscopy using fluorescently labeled RGD‐PEG–L. Therapeutic efficacy of DEXP‐encapsulating RGD‐PEG–L compared with nontargeted liposomes was evaluated in rats with AIA. Results RGD‐PEG–L bound to and were taken up by proliferating human VECs in vitro. In vivo, increased targeting of radiolabeled RGD‐PEG–L to areas of LPS‐induced inflammation in rats was observed. Specific association with the blood vessel wall at the site of inflammation was confirmed by intravital microscopy. One single intravenous injection of DEXP encapsulated in RGD‐PEG–L resulted in a strong and long‐lasting antiarthritic effect in rat AIA. Conclusion RGD‐targeted PEG liposomes represent an endothelial cell–specific drug delivery system that targets VECs at sites of inflammation. Use of these liposomes to deliver DEXP to VECs at arthritis‐affected sites proved efficacious in rat adjuvant arthritis. These data indicate that VECs have an essential role in the inflammation process and suggest the possibility of using VEC targeting for therapeutic intervention in inflammatory processes such as arthritis.