Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.
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.
Shaunak
Sunil
S
Faculty of Medicine, Imperial College London, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK. s.shaunak@imperial.ac.uk
Thomas
Sharyn
S
Gianasi
Elisabetta
E
Godwin
Antony
A
Jones
Emma
E
Teo
Ian
I
Mireskandari
Kamiar
K
Luthert
Philip
P
Duncan
Ruth
R
Patterson
Steve
S
Khaw
Peng
P
Brocchini
Steve
S
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*
D018925:Chemokines; D004338:Drug Combinations; D046911:Macromolecular Substances; D005944:Glucosamine