title: Transdermal deferoxamine prevents pressure-induced diabetic ulcers.
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.
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Dominik
authors.initials: D
authors.lastname: Duscher
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Evgenios
authors.initials: E
authors.lastname: Neofytou
authors.affiliation: Department of Plastic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21201;
authors.forename: Victor W
authors.initials: VW
authors.lastname: Wong
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Zeshaan N
authors.initials: ZN
authors.lastname: Maan
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rennert
authors.affiliation: Biomaterials and Advanced Drug Delivery Center, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Mohammed
authors.identifier: http://orcid.org/0000-0001-7646-1709
authors.initials: M
authors.lastname: Inayathullah
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Michael
authors.initials: M
authors.lastname: Januszyk
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Melanie
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: Biomaterials and Advanced Drug Delivery Center, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Malkovskiy
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Arnetha J
authors.initials: AJ
authors.lastname: Whitmore
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Graham G
authors.identifier: http://orcid.org/0000-0002-9706-8356
authors.initials: GG
authors.lastname: Walmsley
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Michael G
authors.initials: MG
authors.lastname: Galvez
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whittam
authors.affiliation: Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461.
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.affiliation: Biomaterials and Advanced Drug Delivery Center, Stanford University School of Medicine, Stanford, CA 94305; and ggurtner@stanford.edu jayraja@stanford.edu.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; ggurtner@stanford.edu jayraja@stanford.edu.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020405:Dermis / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D048909:Diabetes Complications / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems; D008810:Mice, Inbred C57BL; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011312:Pressure / Q000009:adverse effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D014456:Ulcer / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D003676:Deferoxamine
keywords: angiogenesis; diabetes; drug delivery; small molecule; wound healing