Alpha-methylprednisolone conjugated cyclodextrin polymer-based nanoparticles for rheumatoid arthritis therapy.
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.
Hwang
Jungyeon
J
Insert Therapeutics, Inc., Pasadena, CA 91106, USA.
Rodgers
Kathleen
K
Oliver
James C
JC
Schluep
Thomas
T
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects*; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011108:Polymers / Q000737:chemistry; D016896:Treatment Outcome
D003505:Cyclodextrins; D004337:Drug Carriers; D011108:Polymers; D008775:Methylprednisolone