New research in rats suggests that arginine–glycine–aspartic acid (RGD) peptide liposomes that deliver dexamethasone phosphate (DEXP) directly to sites of inflammation show promise in the treatment of rheumatoid arthritis (RA), according to an article in the April 2006 issue of Arthritis & Rheumatism.1

The new study was designed to investigate whether RGD peptide-exposing polyethylene glycol (PEG) liposomes (RGD-PEG-L) are targeted to adhesion molecules expressed on angiogenic vascular endothelial cells (VECs) and whether the targeted liposomes can then bind to the VECs at sites of inflammation. The RGD peptide was selected due to its high chemical stability and its high affinity for proteins expressed on angiogenic VECs at sites of inflammation. The researchers first used a combination of cell sorting and confocal microscopy to confirm that the RGD-PEG liposomes are internalized in cultured human VECs. In addition, the researchers demonstrated that RGD-PEG liposomes were targeted to sites of lipopolysaccharide (LPS)-induced inflammation in rats, demonstrating that RGD-PEG liposomes are targeted to VECs at sites of inflammation.

Lastly, after the induction of adjuvant arthritis by immunization with heat-inactivated Mycobacterium tuberculosis, rats were randomly divided to receive either a single intravenous injection of 1 mg of DEXP encapsulated in targeted RGD peptide-exposing PEG liposomes (RGD-DEXP-PEG-L) or the same dosage of DEXP encapsulated in non-RGD-targeted PEG liposomes (DEXP-PEG-L). Treatment with RGD-DEXP-PEG-L strongly inhibited disease progression during the first 3 days after treatment and also reduced the peak levels of arthritic severity. Treatment with RGD-DEXP-PEG-L was significantly more efficacious than either non-RGD-targeted or empty RGD-targeted liposomes (P <.05).

"Using these liposomes to deliver DEXP to VECs at sites of arthritis involvement proved very efficacious in rat [adjuvant-induced arthritis], indicating promise for the treatment of RA," note the study's leading authors, Gert Storm, PhD, and Gerben Koning, PhD, of Utrecht University in Utrecht, the Netherlands. "Future research will focus more precisely on the mechanisms involved and may also explore delivery of other anti-inflammatory compounds by the RGD-targeted liposomes."

Inflamed synovium target for novel therapies

To further improve the delivery of both drugs and imaging agents for the treatment of RA, researchers are increasingly focused on the inflamed synovium that leads to joint destruction, explain Toby Garrood, MRCP, MSc, and Constantino Pitzalis, MD, PhD, FRCP, of King's College London School of Medicine in England in an accompanying editorial.2

Liposomes have been successfully used in the imaging of inflamed joints, as well as in drug delivery in RA. The authors note that in one animal model, liposome-encapsulated prednisolone was reported to achieve the effects equivalent to 10-fold higher doses of the free drug3 and that other exciting potential targets within the inflamed joint include synovial macrophages and E-selectin.

Important therapeutic advance

H. Michael Belmont, MD, medical director of New York University Hospital for Joint Disease in New York, NY, tells CIAOMed that "what is interesting is the notion of using liposomes and targeting endothelial cell adhesion to deliver a therapy. It would be nice to be able to deliver medication, such as dexamethasone phosphate, which has a lot of systemic effects in the management of RA, in a more targeted way and get many of the benefits while reducing systemic events." 

The next step is to conduct trials in humans, he says. "What I find exciting is the option of linking alternative therapies to this type of delivery system. We don't necessarily have to just deliver steroids; maybe we deliver a biologic [with this technology]."

References

  1. Koning GA, Schiffelers RM, Wauben MHM, et al. Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate-containing RGD peptide liposomes inhibits experimental arthritis. Arthritis Rheum. 2006;34:1198-1208.
  2. Garrood T, Pitzalis C. Targeting the inflamed synovium: The quest for specificity. Arthritis Rheum. 2006;34:1055-1060.
  3. Metselaar JM, van der Berg WB, Holthuysen AE, et al. Liposomal targeting of glucocorticoids to synovial lining cells strongly increases therapeutic benefit in collagen type II arthritis. Ann Rheum Dis. 2004;63:348-353.