Journal Article

Transdermal deferoxamine prevents pressure-induced diabetic ulcers

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

2015

Overview

Significance Diabetes is the leading cause of nontraumatic amputations. There are no effective therapies to prevent diabetic ulcer formation and only modestly effective technologies to help with their healing. To enhance diabetic wound healing we designed a transdermal delivery system containing the FDA-approved small molecule deferoxamine, an iron chelator that increases defective hypoxia inducible factor-1 alpha transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. This system overcomes the challenge of delivering hydrophilic molecules through the normally impermeable stratum corneum and both prevents diabetic ulcer formation and improves the healing of existing diabetic wounds. This represents a prophylactic pharmacological agent to prevent ulcer formation that is rapidly translatable into the clinic and has the potential to ultimately transform the care and prevention of diabetic complications. 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.

• Publisher: National Academy of Sciences
• Subject: Administration, Cutaneous / Animals / Apoptosis / Apoptosis - drug effects / Biochemistry / Biological Sciences / chelating agents / deferoxamine / Deferoxamine - administration & dosage / Deferoxamine - pharmacology / Deferoxamine - therapeutic use / Dermis - blood supply / Dermis - drug effects / Dermis - pathology / Diabetes / Diabetes Complications - drug therapy / Diabetes Complications - pathology / Diabetes Complications - prevention & control / Diabetes Mellitus, Experimental - drug therapy / Diabetes Mellitus, Experimental - pathology / diabetic complications / Drug Delivery Systems / Engineering / Glucose / hydrophilicity / Hypoxia / hypoxia-inducible factor 1 / Mice, Inbred C57BL / Mortality / Necrosis / Neovascularization, Physiologic - drug effects / oxygen / Patients / Physical Sciences / Pressure - adverse effects / Reactive Oxygen Species - metabolism / Rodents / Stress, Physiological - drug effects / tissue repair / transcriptional activation / Ulcer - drug therapy / Ulcer - pathology / Vascular Endothelial Growth Factor A - metabolism / Wound Healing - drug effects