title: Synthesis and evaluation of a nanoglobular dendrimer 5-aminosalicylic Acid conjugate with a hydrolyzable schiff base spacer for treating retinal degeneration.
abstract: Biocompatible dendrimers with well-defined nanosizes are increasingly being used as carriers for drug delivery. 5-Aminosalicylic acid (5-ASA) is an FDA-approved therapeutic agent recently found effective in treating retinal degeneration of animal models. Here, a water-soluble dendrimer conjugate of 5-ASA (AGFB-ASA) was designed to treat such retinal degeneration. The drug was conjugated to a generation 2 (G2) lysine dendrimer with a silsesquioxane core (nanoglobule) by using a hydrolyzable Schiff base spacer. Incubation of nanoglobular G2 dendrimer conjugates containing a 4-formylbenzoate (FB) Schiff base spacer in pH 7.4 phosphate buffers at 37 °C gradually released 5-ASA. Drug release from the dendrimer conjugate was significantly slower than from the low molecular weight free Schiff base of 5-ASA (FB-ASA). 5-ASA release from the dendrimer conjugate was dependent on steric hindrance around the spacer. After intraperitoneal injection, the nanoglobular 5-ASA conjugate provided more effective 7-day protection against light-induced retinal degeneration at a reduced dose than free 5-ASA in Abca4(-/-)Rdh8(-/-) mice. The dendrimer 5-ASA conjugate with a degradable spacer could be a good candidate for controlled delivery of 5-ASA to the eye for treatment of retinal degeneration.
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Case Western Reserve University , Cleveland, Ohio, United States.
authors.forename: Xueming
authors.initials: X
authors.lastname: Wu
authors.forename: Guanping
authors.initials: G
authors.lastname: Yu
authors.forename: Chengcai
authors.initials: C
authors.lastname: Luo
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Da
authors.initials: D
authors.lastname: Sun
authors.forename: Zhuxian
authors.initials: Z
authors.lastname: Zhou
authors.forename: Anthony
authors.initials: A
authors.lastname: Puntel
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D050091:Dendrimers / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D019804:Mesalamine / Q000737:chemistry / Q000627:therapeutic use*; D049329:Nanostructures; D012162:Retinal Degeneration / Q000188:drug therapy*; D012545:Schiff Bases / Q000737:chemistry*
chemical_list: D050091:Dendrimers; D012545:Schiff Bases; D019804:Mesalamine