Dextrin-rhEGF conjugates as bioresponsive nanomedicines for wound repair

J Control Release. 2008 Sep 24;130(3):275-83. doi: 10.1016/j.jconrel.2008.07.023. Epub 2008 Jul 22.


Growth factors are known to act in concert to promote wound repair, but their topical application rarely leads to a significant clinical improvement of chronic wounds due to premature inactivation in wound environment. The aim of this study was to synthesise a polymer-growth factor conjugate and investigate whether the novel concept called Polymer-masking-UnMasking-Protein Therapy (PUMPT) might be used to generate bioresponsive polymer therapeutics as nanomedicines able to promote tissue repair. Succinoylated dextrin ( approximately 85,000 g/mol; approximately 19 mol% succinoylation), and rhEGF were chosen as a first model combination. The conjugate synthesised contained approximately 16%wt rhEGF and <1% free protein. It exhibited increased stability towards proteolytic degradation by trypsin and the clinically relevant enzyme neutrophil elastase. The dextrin component was degraded on addition of alpha-amylase leading to sustained release of free rhEGF over time (52.7% release after 168 h). When biological activity was assessed (+/-alpha-amylase) in proliferation assays using epidermoid carcinoma (HEp2) cells and HaCaT keratinocytes, as anticipated, polymer conjugation reduced rhEGF bioactivity (p=0.0035). However, exposure to physiological concentrations of alpha-amylase triggered dextrin degradation and this led to protein unmasking with restoration of bioactivity to the level seen for unmodified rhEGF. Indeed, prolongation of HEp2 proliferation was observed over 8 days. The inability of dextrin, succinoylated dextrin or alpha-amylase alone to induce proliferative effects, and the ability of alpha-amylase-exposed dextrin-rhEGF to induce phosphorylation of the epidermal growth factor receptor (EGFR) in HEp2 cells confirmed a mechanism of action by stimulation of classical signal transduction pathways. These observations suggest that this dextrin-rhEGF, and other dextrin-growth factor conjugates have potential for further development as bioresponsive nanomedicines for tissue repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocatalysis
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Delayed-Action Preparations / chemical synthesis
  • Delayed-Action Preparations / chemistry
  • Delayed-Action Preparations / pharmacology
  • Dextrins / chemistry*
  • Drug Delivery Systems / methods*
  • Drug Stability
  • Epidermal Growth Factor / administration & dosage*
  • Epidermal Growth Factor / chemistry
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Kinetics
  • Leukocyte Elastase / chemistry
  • Molecular Weight
  • Nanomedicine / methods*
  • Phosphorylation / drug effects
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / pharmacology
  • Spectroscopy, Fourier Transform Infrared
  • Succinic Anhydrides / chemistry
  • Wound Healing / drug effects
  • Wound Healing / physiology*
  • alpha-Amylases / chemistry


  • Delayed-Action Preparations
  • Dextrins
  • Prodrugs
  • Recombinant Proteins
  • Succinic Anhydrides
  • Epidermal Growth Factor
  • succinic anhydride
  • EGFR protein, human
  • ErbB Receptors
  • alpha-Amylases
  • Leukocyte Elastase