Development of a poly(ether urethane) system for the controlled release of two novel anti-biofilm agents based on gallium or zinc and its efficacy to prevent bacterial biofilm formation

J Control Release. 2013 Dec 28;172(3):1035-44. doi: 10.1016/j.jconrel.2013.10.005. Epub 2013 Oct 17.


Traditional antibiotic therapy to control medical device-based infections typically fails to clear biofilm infections and may even promote the evolution of antibiotic resistant species. We report here the development of two novel antibiofilm agents; gallium (Ga) or zinc (Zn) complexed with protoporphyrin IX (PP) or mesoprotoporphyrin IX (MP) that are both highly effective in negating suspended bacterial growth and biofilm formation. These chelated gallium or zinc complexes act as iron siderophore analogs, supplanting the natural iron uptake of most bacteria. Poly (ether urethane) (PEU; Biospan®) polymer films were fabricated for the controlled sustained release of the Ga- or Zn-complexes, using an incorporated pore-forming agent, poly(ethylene glycol) (PEG). An optimum formulation containing 8% PEG (MW=1450) in the PEU polymer effectively sustained drug release for at least 3months. All drug-loaded PEU films exhibited in vitro ≥ 90% reduction of Gram-positive (Staphylococcus epidermidis) and Gram-negative (Pseudomonas aeruginosa) bacteria in both suspended and biofilm culture versus the negative control PEU films releasing nothing. Cytotoxicity and endotoxin evaluation demonstrated no adverse responses to the Ga- or Zn-complex releasing PEU films. Finally, in vivo studies further substantiate the anti-biofilm efficacy of the PEU films releasing Ga- or Zn- complexes.

Keywords: Anti-biofilm biomaterials; Interrupting iron metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Biofilms / drug effects*
  • Coordination Complexes / administration & dosage
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology
  • Delayed-Action Preparations / chemistry*
  • Female
  • Gallium / administration & dosage*
  • Gallium / chemistry
  • Gallium / pharmacology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Polyurethanes / chemistry*
  • Prosthesis-Related Infections / prevention & control*
  • Protoporphyrins / administration & dosage
  • Protoporphyrins / chemistry
  • Protoporphyrins / pharmacology
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / physiology
  • Staphylococcus epidermidis / drug effects
  • Staphylococcus epidermidis / physiology
  • Zinc / administration & dosage*
  • Zinc / chemistry
  • Zinc / pharmacology


  • Anti-Bacterial Agents
  • Coordination Complexes
  • Delayed-Action Preparations
  • Polyurethanes
  • Protoporphyrins
  • polyetherurethane
  • protoporphyrin IX
  • Gallium
  • Zinc