Alpha-methylprednisolone conjugated cyclodextrin polymer-based nanoparticles for rheumatoid arthritis therapy

• Published in: International journal of nanomedicine 2008-01, Vol.3 (3), p.359-371
• Main Authors: Hwang, Jungyeon, Rodgers, Kathleen, Oliver, James C, Schluep, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - pathology; Cell Proliferation - drug effects; Cells, Cultured; cyclodextrin polymer (CDP); Cyclodextrins - administration & dosage; Cyclodextrins - chemistry; Drug Carriers - chemistry; enhanced permeability and retention effect (EPR); Humans; Lymphocytes - cytology; Lymphocytes - drug effects; Methylprednisolone - administration & dosage; Methylprednisolone - chemistry; Mice; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Original Research; polymer conjugate (CDP-MP); Polymers; Polymers - chemistry; Rheumatoid arthritis; rheumatoid arthritis (RA); Treatment Outcome; α-methylprednisolone (MP)
• ISSN: 1176-9114; 1178-2013; 1178-2013
• DOI: 10.2147/IJN.S3217

A glycinate derivative of alpha-methylprednisolone (MP) was prepared and conjugated to a linear cyclodextrin polymer (CDP) with a loading of 12.4% w/w. The polymer conjugate (CDP-MP) self-assembled into nanoparticles with a size of 27 nm. Release kinetics of MP from the polymer conjugate showed a half-life (t1/2) of 50 h in phosphate buffer solution (PBS) and 19 h in human plasma. In vitro, the proliferation of human lymphocytes was suppressed to a similar extent but with a delayed effect when CDP-MP was compared with free MP. In vivo, CDP-MP was administered intravenously to mice with collagen-induced arthritis and compared with free MP. CDP-MP was administered weekly for six weeks (0.07, 0.7, and 7 mg/kg/week) and MP was administered daily for six weeks (0.01, 0.1, and 1 mg/kg/day). Body weight changes were minimal in all animals. After 28 days, a significant decrease in arthritis score was observed in animals treated weekly with an intermediate or high dose of CDP-MP. Additionally, dorsoplantar swelling was reduced to baseline in animals treated with CDP-MP at the intermediate and high dose level. Histological evaluation showed a reduction in synovitis, pannus formation and disruption of architecture at the highest dose level of CDP-MP. MP administered daily at equivalent cumulative doses showed minimal efficacy in this model. This study demonstrates that conjugation of MP to a cyclodextrin-polymer may improve its efficacy, leading to lower doses and less frequent administration for a safer and more convenient management of rheumatoid arthritis.