title: Ionic complex systems based on hyaluronic acid and PEGylated TNF-related apoptosis-inducing ligand for treatment of rheumatoid arthritis.
abstract: 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.
authors.affiliation: Department of Chemical Engineering, College of Engineering, Kyung Hee University, Gyeonggi-do 449-701, South Korea.
authors.forename: Yu-Jeong
authors.initials: YJ
authors.lastname: Kim
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Jin
authors.forename: M
authors.initials: M
authors.lastname: Sivasubramanian
authors.forename: Sohee
authors.initials: S
authors.lastname: Son
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Choi
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.forename: Ick
authors.initials: I
authors.lastname: Chan Kwon
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004058:Diffusion / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007477:Ions; D007700:Kinetics; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000627:therapeutic use; D010316:Particle Size; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D013154:Spleen / Q000166:cytology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D016207:Cytokines; D007477:Ions; D053221:TNF-Related Apoptosis-Inducing Ligand; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid