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.
Kim
Yu-Jeong
YJ
Department of Chemical Engineering, College of Engineering, Kyung Hee University, Gyeonggi-do 449-701, South Korea.
Chae
Su Young
SY
Jin
Cheng-Hao
CH
Sivasubramanian
M
M
Son
Sohee
S
Choi
Ki Young
KY
Jo
Dong-Gyu
DG
Kim
Kwangmeyung
K
Chan Kwon
Ick
I
Lee
Kang Choon
KC
Park
Jae Hyung
JH
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
D016207:Cytokines; D007477:Ions; D053221:TNF-Related Apoptosis-Inducing Ligand; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid