Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis

Abra H Shen,Arash Momeni,Dung H Nguyen,Shamik Mascharak,Geoffrey C Gurtner,Mimi R Borrelli,Ronak A Patel,Michael T Longaker,Derrick C Wan,Sandeep Adem,Nestor M Diaz Deleon,Blake Y Sun,Sara J Yen,Walter L Taylor,Michael Januszyk

doi:10.1038/s41598-020-69293-4

Abstract

Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.

Highlights

Radiation therapy can result in pathological fibrosis of healthy soft tissue
The pathogenesis of radiation-induced skin fibrosis (RIF) is multifactorial and remains incompletely understood; emerging evidence has suggested that targeting pathways of inflammation, cell death, and reactive oxygen species (ROS) generation may mitigate the effects of radiation[8]
Other key factors contributing to excessive soft tissue fibrosis include activation of fibroblasts and damage to microvascular endothelial cells[11,12,13], which are both exacerbated by ROS a ctivity[14,15,16,17,18,19]

Summary

Introduction

Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. We evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. Transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients. Acute skin damage may progress to radiation-induced skin fibrosis (RIF) over weeks to years, characterized by dermal induration and microvascular intimal thickening, leading to hypoperfusion and h ypoxia[2,3,4,5,6,7]. There have been multiple investigations into the therapeutic effects of iron chelators and wound healing

Methods

Results

Conclusion