ENDOTAG-1®, A CATIONIC LIPOSOMECONTAINING PACLITAXEL, DEMONSTRATES ANTI-ANGIOGENIC AND ANTI-INFLAMMATORY ACTIVITY IN RHEUMATOID ARTHRITIS IN VIVO

Abstract

Introduction: Inflammation and angiogenesis are hallmarks of rheumatoid arthritis (RA) that contribute largely to the formation of pannus tissue and joint destruction in patients suffering from RA. We have recently shown that intravenously applied cationic liposomes target efficiently angiogenic endothelial cells in the synovial vasculature of rheumatoid joints and therefore may also serve as potent vehicles for systemic drug delivery and therapy in RA. Therefore the aim of our study was to quantify the antiangiogenic and antiinflammatory properties of EndoTAG-1^® (paclitaxel formulated in cationic liposomes) in the inflamed joints of murine models of RA and to compare the therapeutical efficacy of EndoTAG-1^® to Taxol^® (paclitaxel in Cremophor EL).

Materials and Methods: Targeting of fluorescently labelled cationic liposomes to the synovial vasculature in mice with antigen-induced arthritis (AIA) was analysed by intravital microscopy. Density of functional vessels and adhesion of fluorescently labelled platelets or leukocytes were determined after treatment with EndoTAG-1^®. Knees were subjected to clinical scoring and histopathological analysis.

Results: EndoTAG-1^® treatment of AIA mice with developing or in established disease showed a strong attenuation of the course of the disease as well as a potent anti-inflammatory effect. Histological analysis of knee sections demonstrated a dramatic reduction of the pannus and infiltration of inflammatory cells. Enrichment of EndoTAG at the synovial vasculature of AIA mice was observed when compared with healthy mice. Treatment of AIA mice with EndoTAG-1^® concomitant to disease induction showed a complete remission of the course of the disease as shown by a significant decrease of clinical scores compared to both control and Taxol^® treated groups. A complete inhibition (98%) of neo-vascularisation was observed in the synovial vasculature of mice with AIA that were treated with EndoTAG-1^® whereas Taxol^® alone showed only 50% inhibitory effect. Rolling and adhesion of platelets were reduced to 53% (paclitaxel 5%) and 98% (paclitaxel 57%), respectively.

Discussion: Our in vivo data clearly demonstrates that anti-angiogenic and anti-inflammatory activity of Endo-TAG-1^® contribute to the therapeutical efficacy of this drug in RA. Notably, therapeutic efficacy with Endo-TAG-1^® was superior to Taxol^®. This strongly suggests that systemic delivery of cationic liposomes is very well suited to enrich compounds to rheumatoid joints for therapy and could be a promising treatment option for RA.