Dual-targeted hybrid micelles mediated by VCAM-1 suppress synovial angiogenesis in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovitis and the formation of pannus, leading to proliferation of synovial tissue and destruction of bone and cartilage. Traditional drug therapy is often limited by the lack of drug targeting and the continuous synovial angiogenesis. Herein, a dual-targeted micelles for macrophages and vascular endothelial cells with excellent anti-inflammatory and anti-angiogenic properties was constructed to effectively treat RA.

We developed vascular cell adhesion molecule-1 (VCAM-1) binding peptide modified polyphyllin I (PPI) loaded micelles (VM-PE@Ms) in which eucommia ulmoides polysaccharide (EUP) was used as the hydrophilic parts of the hybrid micelles. The targeting, ROS scavenging effect, anti-inflammatory activity, and inhibition of angiogenesis of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was employed to explore targeting, impact on inflammatory cytokine levels, and cartilage protective effect of the micelles in vivo.

VM-PE@Ms. exhibited targeting to both activated RAW264.7 cells and human umbilical vein endothelial cells (HUVECs), and strong inhibitory effect of inflammatory cytokine secretion, ROS generation, and angiogenesis. In vivo assays demonstrated that VM-PE@Ms. displayed desirable pharmacodynamics property, which was confirmed by precise inflammatory joint targeting and retention capacity and bone erosion remission effects and was related to suppression of inflammation and synovial angiogenesis.

In summary, the proposed dual-targeted hybrid micelles have the potential role for anti-inflammatory and anti-angiogenic therapy of RA.