Transdermal deferoxamine prevents pressure-induced diabetic ulcers

Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):94-9. doi: 10.1073/pnas.1413445112. Epub 2014 Dec 22.

Abstract

There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

Keywords: angiogenesis; diabetes; drug delivery; small molecule; wound healing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Animals
  • Apoptosis / drug effects
  • Deferoxamine / administration & dosage
  • Deferoxamine / pharmacology
  • Deferoxamine / therapeutic use*
  • Dermis / blood supply
  • Dermis / drug effects
  • Dermis / pathology
  • Diabetes Complications / drug therapy*
  • Diabetes Complications / pathology
  • Diabetes Complications / prevention & control*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / pathology
  • Drug Delivery Systems
  • Mice, Inbred C57BL
  • Necrosis
  • Neovascularization, Physiologic / drug effects
  • Pressure / adverse effects*
  • Reactive Oxygen Species / metabolism
  • Stress, Physiological / drug effects
  • Ulcer / drug therapy*
  • Ulcer / pathology
  • Vascular Endothelial Growth Factor A / metabolism
  • Wound Healing / drug effects

Substances

  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • Deferoxamine