title: Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.
abstract: Dendrimers are hyperbranched macromolecules that can be chemically synthesized to have precise structural characteristics. We used anionic, polyamidoamine, generation 3.5 dendrimers to make novel water-soluble conjugates of D(+)-glucosamine and D(+)-glucosamine 6-sulfate with immuno-modulatory and antiangiogenic properties respectively. Dendrimer glucosamine inhibited Toll-like receptor 4-mediated lipopolysaccharide induced synthesis of pro-inflammatory chemokines (MIP-1 alpha, MIP-1 beta, IL-8) and cytokines (TNF-alpha, IL-1 beta, IL-6) from human dendritic cells and macrophages but allowed upregulation of the costimulatory molecules CD25, CD80, CD83 and CD86. Dendrimer glucosamine 6-sulfate blocked fibroblast growth factor-2 mediated endothelial cell proliferation and neoangiogenesis in human Matrigel and placental angiogenesis assays. When dendrimer glucosamine and dendrimer glucosamine 6-sulfate were used together in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery, they increased the long-term success of the surgery from 30% to 80% (P = 0.029). We conclude that synthetically engineered macromolecules such as the dendrimers described here can be tailored to have defined immuno-modulatory and antiangiogenic properties, and they can be used synergistically to prevent scar tissue formation.
authors.affiliation: Faculty of Medicine, Imperial College London, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK. s.shaunak@imperial.ac.uk
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaunak
authors.forename: Sharyn
authors.initials: S
authors.lastname: Thomas
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gianasi
authors.forename: Antony
authors.initials: A
authors.lastname: Godwin
authors.forename: Emma
authors.initials: E
authors.lastname: Jones
authors.forename: Ian
authors.initials: I
authors.lastname: Teo
authors.forename: Kamiar
authors.initials: K
authors.lastname: Mireskandari
authors.forename: Philip
authors.initials: P
authors.lastname: Luthert
authors.forename: Ruth
authors.initials: R
authors.lastname: Duncan
authors.forename: Steve
authors.initials: S
authors.lastname: Patterson
authors.forename: Peng
authors.initials: P
authors.lastname: Khaw
authors.forename: Steve
authors.initials: S
authors.lastname: Brocchini
mesh_terms: D000818:Animals; D002387:Cataract Extraction / Q000009:adverse effects / Q000379:methods; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002921:Cicatrix / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005944:Glucosamine / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D046911:Macromolecular Substances / Q000008:administration & dosage / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011817:Rabbits; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D018925:Chemokines; D004338:Drug Combinations; D046911:Macromolecular Substances; D005944:Glucosamine