Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis

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.

A comparative analysis of deferoxamine treatment modalities for dermal radiation‐induced fibrosis

“…Paralleling previously published work, injection of DFO in the post‐recovery chronic phase increased laser Doppler measured perfusion and histologic vascularity 12 . Continuous patch treatment was also noted to yield the greatest effect, as similarly shown by Shen et al 13 Since endothelial damage is both a product of radiation injury and a catalyst of fibrosis development, preservation of perfusion may contribute, at least in part, to the improved fibrosis measures observed 10 …”

“…Of note, we observed an increase in perfusion early following radiation therapy. While this was not observed by Shen et al, 13 site‐specific differences in skin, as well as standardized conditions for measurement, may have contributed to this discrepancy. Furthermore, our findings in this present manuscript parallel histologic findings by others, showing acute radiation exposure increasing vascular permeability and transient pathologic blooming of irregular capillaries 42,43 …”

“…Second, chelation of free iron decreases oxidative damage by limiting Fenton‐based ROS generation, which is dependent on ferric iron as a catalyst 19‐21 . As inflammatory reactions self‐perpetuate in radiation toxicity, the multi‐pronged benefits of DFO administration have been shown in preclinical studies to not only reverse RIF, but also minimize the damage that would have occurred when given prior to the onset of fibrosis 13 . Aside from symptomatic treatment, there are very few approved therapies for RIF treatment and prevention.…”

“…The iron‐chelating agent, deferoxamine (DFO), has emerged as a potential therapeutic for improving RIF of the skin in murine subjects 12,13 . DFO addresses multiple pathogenic mechanisms of the fibrotic reaction within the dermis following irradiation (IR).…”

Radiation-Induced Tissue Damage: Clinical Consequences and Current Treatment Options

“…[129][130][131] The potential role of DFO in the treatment of RIF was demonstrated recently with evidence that radiated mice treated with transdermal DFO had significantly improved skin perfusion and reduced dermal thickness akin to nonirradiated tissue. 132…”