Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation

Nat Biotechnol. 2004 Aug;22(8):977-84. doi: 10.1038/nbt995. Epub 2004 Jul 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cataract Extraction / adverse effects
  • Cataract Extraction / methods
  • Cell Line
  • Cell Proliferation
  • Cells, Cultured
  • Chemokines / metabolism
  • Cicatrix / diagnosis
  • Cicatrix / etiology
  • Cicatrix / prevention & control*
  • Dendritic Cells / drug effects*
  • Dendritic Cells / metabolism
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Endothelial Cells / drug effects*
  • Endothelial Cells / physiology
  • Glucosamine / administration & dosage*
  • Glucosamine / chemistry
  • Humans
  • Macromolecular Substances / administration & dosage
  • Macromolecular Substances / chemistry
  • Neovascularization, Pathologic / prevention & control*
  • Rabbits
  • Treatment Outcome
  • Wound Healing / drug effects*

Substances

  • Chemokines
  • Drug Combinations
  • Macromolecular Substances
  • Glucosamine