Development of heparin-based nanoparticles with multi-functional biological properties intended for rheumatoid arthritis therapy

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This study aimed to develop a nano-sized drug carrier consisting of heparin, which has a variety of biological functions, and apply it to rheumatoid arthritis therapy. First, we conjugated native heparin or partially ring-opened heparin with sphingosine. These sphingosine-heparin conjugates form a self-assembling nanoparticle in water, which has the diameter of 120-200 nm and the ζpotential of -50 to -60 mV. Although inflammatory cytokines were produced following stimulation of mouse peritoneal macrophages with lipopolysaccharides, co-presence of the sphingosine-heparin conjugates, even without any drugs, significantly reduced the cytokine production. On the other hand, sphingosine-heparin conjugates were not effective against poly I:poly C-induced TNF-α production, suggesting that the conjugates act selectively on the TLR4/NF-κB pathway. In the mouse model of type II collagen-induced arthritis, the sphingosine-heparin conjugates, especially that derived from partially ring-opened heparin, showed remarkable anti-inflammatory effects.