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- Title
Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.
- Authors
Shaunak, Sunil; Thomas, Sharyn; Gianasi, Elisabetta; Godwin, Antony; Jones, Emma; Teo, Ian; Mireskandari, Kamiar; Luthert, Philip; Duncan, Ruth; Patterson, Steve; Khaw, Peng; Brocchini, Steve
- 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-1a, MIP-1ß, IL-8) and cytokines (TNF-a, IL-1ß, 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.
- Subjects
DENDRIMERS; GLUCOSAMINE; MACROMOLECULES; TISSUES; CHEMOKINES; DISEASES
- Publication
Nature Biotechnology, 2004, Vol 22, Issue 8, p977
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt995