Transdermal deferoxamine prevents pressure-induced diabetic ulcers

Dominik Duscher, Evgenios Neofytou, Victor W. Wong, Zeshaan N. Maan, Robert C. Rennert, Mohammed Inayathullah, Michael Januszyk, Melanie Rodrigues, Andrey V. Malkovskiy, Arnetha J. Whitmore, Graham G. Walmsley, Michael G. Galvez, Alexander J. Whittam, Michael Brownlee, Jayakumar Rajadas, Geoffrey C. Gurtner

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)94-99
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number1
DOIs
StatePublished - Jan 6 2015

Fingerprint

Hypoxia-Inducible Factor 1
Deferoxamine
Ulcer
Pressure
Pressure Ulcer
Wound Healing
Drug Delivery Systems
Transcriptional Activation
Iron
Heel
Chelating Agents
Free Radicals
Reactive Oxygen Species
Cell Death
Transcription Factors
Collagen
Extremities
Oxygen
Glucose
Mortality

Keywords

  • Angiogenesis
  • Diabetes
  • Drug delivery
  • Small molecule
  • Wound healing

ASJC Scopus subject areas

  • General

Cite this

Duscher, D., Neofytou, E., Wong, V. W., Maan, Z. N., Rennert, R. C., Inayathullah, M., ... Gurtner, G. C. (2015). Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proceedings of the National Academy of Sciences of the United States of America, 112(1), 94-99. https://doi.org/10.1073/pnas.1413445112

Transdermal deferoxamine prevents pressure-induced diabetic ulcers. / Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W.; Maan, Zeshaan N.; Rennert, Robert C.; Inayathullah, Mohammed; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V.; Whitmore, Arnetha J.; Walmsley, Graham G.; Galvez, Michael G.; Whittam, Alexander J.; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 1, 06.01.2015, p. 94-99.

Research output: Contribution to journalArticle

Duscher, D, Neofytou, E, Wong, VW, Maan, ZN, Rennert, RC, Inayathullah, M, Januszyk, M, Rodrigues, M, Malkovskiy, AV, Whitmore, AJ, Walmsley, GG, Galvez, MG, Whittam, AJ, Brownlee, M, Rajadas, J & Gurtner, GC 2015, 'Transdermal deferoxamine prevents pressure-induced diabetic ulcers', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 1, pp. 94-99. https://doi.org/10.1073/pnas.1413445112
Duscher, Dominik ; Neofytou, Evgenios ; Wong, Victor W. ; Maan, Zeshaan N. ; Rennert, Robert C. ; Inayathullah, Mohammed ; Januszyk, Michael ; Rodrigues, Melanie ; Malkovskiy, Andrey V. ; Whitmore, Arnetha J. ; Walmsley, Graham G. ; Galvez, Michael G. ; Whittam, Alexander J. ; Brownlee, Michael ; Rajadas, Jayakumar ; Gurtner, Geoffrey C. / Transdermal deferoxamine prevents pressure-induced diabetic ulcers. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 1. pp. 94-99.
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