Ionic complex systems based on hyaluronic acid and PEGylated TNF-related apoptosis-inducing ligand for treatment of rheumatoid arthritis

The clinical applications of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), an emerging therapeutic protein for cancer and rheumatoid arthritis (RA), are limited by its instability and short biological half-life. In this study, efficient therapeutic modalities for RA treatment were developed in the form of nano-sized complexes (nanocomplexes) based on hyaluronic acid (HA) and polyethylene glycol (PEG)–derivatized TRAIL (PEG–TRAIL) formed by N-terminal specific PEGylation. The nanocomplexes were prepared by simply mixing the positively charged PEG–TRAIL and negatively charged HA, and showed negligible loss of bioactivity compared with the PEG–TRAIL. The in vivo biodistribution and diffusion kinetics of Cy5.5-labeled PEG–TRAIL in mice were observed using a near-infrared optical imaging system after subcutaneous injection of three different formulations: PEG–TRAIL in phosphate–buffered saline (PBS, pH 7.4), nanocomplex in PBS, or nanocomplex in 1% HA solution. The results suggested that PEG–TRAIL is released slowly in vivo from the nanocomplex in 1% HA. Experiments in a collagen-induced arthritis mouse model demonstrated that the magnitudes of therapeutic effects, as judged by clinical scores and histology, were significantly enhanced by the sustained delivery of PEG–TRAIL, with the order of nanocomplex in 1% HA > nanocomplex in PBS > PEG–TRAIL in PBS. In addition, sustained delivery of PEG–TRAIL from the nanocomplex in 1% HA resulted in significant reduction of serum inflammatory cytokines and collagen-specific antibodies that are responsible for the pathogenesis of RA. These results imply that HA/PEG–TRAIL nanocomplex formulations are promising therapeutic modalities for the treatment of RA.