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.wound healing | diabetes | drug delivery | small molecule | angiogenesis D iabetes mellitus affects over 25 million people in the United States (1, 2) and costs nearly $250 billion per year (3). Chronic diabetic wounds and decubiti are important long-term sequalae of both diabetes mellitus types 1 and 2 (4). There is a high mortality in diabetic patients who develop decubiti (5-7), and owing to prolonged disability and the high rates of recurrence these wounds represent an especially severe complication of diabetes (8). This is further underscored by the fact that diabetic nonhealing wounds are the leading cause of nontraumatic amputations in the United States (3, 9-11). As such, there is a clear need for new approaches to effectively manage and treat diabetic ulcers.The propensity for wound development in diabetes is associated with a reduced capacity for ischemia-driven neovascularization (12, 13). Hypoxia inducible factor-1 (HIF-1), which consists of a highly regulated α-subunit and a constitutively expressed β-subunit, is a critical transcriptional regulator of the normal cellular response to hypoxia, promoting progenitor cell recruitment, proliferation, survival, and neovascularization (14, 15). In nondiabetics, hypoxia causes stabilization of HIF-1α protein by preventing the normal rapid proteasomal degradation of HIF-1α. It does this by inhibiting the prolyl hydroxylases (PHDs), which hydroxylate specific prolyl residues on HIF-1α. Without proline hydroxylation HIF-1α is not ...

PKCδ inhibition normalizes the wound-healing capacity of diabetic human fibroblasts

“…However, our findings also suggest that the abnormalities of the response of fibroblasts to hypoxia could be a contributing factor. Previous studies identified activation of hypoxia-inducible factor 1α and its inhibition by p300 as an important pathway that is abnormal in fibroblasts from diabetic patients, the normalization of which could improve wound healing (54,55). Thus, it is likely that abnormalities in wound healing, especially in fibroblasts, are caused by several important pathways that may be related to such phenomena as hyperglycemia, insulin resistance, and oxidative stress.…”

Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats

“…Hypoxia has been shown to induce the production of cytokines and stimulate the proliferation and migration of fibroblasts and keratinocytes and local hypoxia in wounds could accelerate wound closure mediated by the HIF-1 (Li et al, 2007;Shen et al, 2009). Deferoxamine, an iron chelator has been used for the induction of HIF-1α accumulation even under normoxia (Martinez-Romero et al, 2008;Wu et al, 2010;Duscher et al, 2015). Notwithstanding the HIF-1α inducing property of deferoxamine and its indirect effect on several vital cellular processes, there is no available report on the effect of deferoxamine on diabetic wound healing after topical application.…”

“…HIF-1α is a master transcription factor, which not only activates VEGF expression, but a number of other genes also, that are important to wound healing (Rey and Semenza, 2010). Additionally, HIF-1α regulates many target genes involved in angiogenesis and has been reported to be reduced in the diabetic environment that may contribute to impaired wound healing (Botusan et al, 2008, Xing et al, 2011Duscher et al, 2015). In this study, topical application of deferoxamine significantly increased HIF-1α mRNA and protein levels from day 3 onwards and accelerated wound healing by stimulating vascularization through up-regulation of VEGF and SDF-1α in an HIF-1α-dependent manner.…”

Black, White, and Gray: Macrophages in Skin Repair and Disease

“…This generates a hypoxic microenvironment 34,35 . Degranulation of platelets and mast cells in the plug along with hypoxia-inducible factors release more than three hundred active substances including cytokines, chemokines, inflammatory mediators and bioactive molecules within minutes to 5 days after injury, drawing in neutrophils and monocytes, and activating macrophages within the wound 36,37 .…”

“…These macrophages release tumor necrosis factor (TNF-α) and hydroxyl radicals, bringing about senescence in fibroblasts 92 . Iron chelators such as deferoxamine are FDA-approved for systemic use in patients with hemoglobinapathies 35 . Their indication can be extended to chronic wounds with iron-overload to reduce local macrophage-induced inflammation and promote the healing response.…”