Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation
Sunil Shaunak1, Sharyn Thomas1, Elisabetta Gianasi1, Antony Godwin2, Emma Jones3, Ian Teo1, Kamiar Mireskandari3, Philip Luthert4, Ruth Duncan5, Steve Patterson6, Peng Khaw3 & Steve Brocchini2
1 Faculty of Medicine, Imperial College London, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK.
2 Biomedical Polymers Group, School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK.
3 Wound Healing Research Unit, Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.
4 Department of Histopathology, Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.
5 Center for Polymer Therapeutics, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
6 Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.
Correspondence should be addressed to Sunil Shaunak s.shaunak@imperial.ac.uk
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, MIP-1, IL-8) and cytokines (TNF-, IL-1, 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.
Nature Biotechnology 22, 977 - 984 (2004)
Published online: 18 July 2004; | doi:10.1038/nbt995 |
