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-1α, MIP-1β, IL-8) and cytokines (TNF-α, IL-1β, 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.
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This study was supported by grants to S.S. from the National Institutes of Health (1-R21-A144694-01), The Wellcome Trust (068309) and The Wolfson Foundation (PR/013217). P.K. is supported, in part, by Moorfields Trustees, The Michael & Ilse Katz Foundation and an Alcon Research Institute Award.
S.S., E.G. and R.D. are inventors on a patent in which the US National Institutes of Health have an interest. This patent has been assigned to a new university spinout company called Polytherics in which The Wellcome Trust, Imperial College London, University College London, School of Pharmacy London, S.B. and S.S. hold equity.
Detailed conjugation and characterisation procedures (PDF 105 kb)
Matrigel assay (PDF 84 kb)
Glaucoma filtration surgery (PDF 140 kb)
Multigene chemokine plasmid for RT-PCR (PDF 297 kb)
Real-time mRNA PCR for human chemokines and cytokines (PDF 100 kb)
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Shaunak, S., Thomas, S., Gianasi, E. et al. Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation. Nat Biotechnol 22, 977–984 (2004). https://doi.org/10.1038/nbt995
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