title: Syntheses of click PEG-dexamethasone conjugates for the treatment of rheumatoid arthritis.
abstract: A novel linear multifunctional polyethylene glycol (PEG)-dexamethasone (Dex) conjugate (click PEG-Dex) was synthesized using facile Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a click reaction). Dex was conjugated to the click PEG via an acid-labile hydrazone bond to allow the drug release in a pathophysiological environment. To evaluate click PEG's potential as a versatile drug delivery platform, the click PEG-Dex conjugates were tested in an adjuvant-induced arthritis (AA) rat model. In vivo optical imaging data confirmed the arthrotropism of the conjugates in the arthritic rats. A long-term treatment study revealed that a single click PEG-Dex conjugate administration provided sustained (>15 days) amelioration of ankle joint inflammation to the AA rats. Treatment with an equivalent dose of dexamethasone phosphate sodium (free Dex) only provided temporal resolution of the arthritis, which recurred upon treatment withdrawal. Further histological and bone mineral density comparison between the ankle joints from both click PEG-Dex and free Dex treatment groups confirmed the superior anti-inflammatory and disease modifying effects of the novel polymer-drug conjugates.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Liu
authors.forename: Ling-dong
authors.initials: LD
authors.lastname: Quan
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.forename: Frederic C
authors.initials: FC
authors.lastname: Laquer
authors.forename: Pawel
authors.initials: P
authors.lastname: Ciborowski
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D002384:Catalysis; D057930:Click Chemistry / Q000379:methods*; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D012995:Solubility
chemical_list: D000893:Anti-Inflammatory Agents; D011092:Polyethylene Glycols; D003907:Dexamethasone