Transdermal Deferoxamine Mitigates Radiation-induced Skin Fibrosis
Mimi R. Borrelli, MBBS, MSc, Sandeep Adem, MS, Nestor M. Deleon Diaz, Shamik Mascharak, BS, Michael Januszyk, MD, PhD, Dung Nguyen, MD, Arash Momeni, MD, PhD, Geoffrey C. Gurtner, MD, Michael T. Longaker, MD, MA, Derrick C. Wan, MD.
Stanford, menlo park, CA, USA.
Background: Radiation therapy (RT) is an important curative and palliative treatment for several types of cancer, but pathological and progressive skin fibrosis is an inevitable and unfavorable side effect. Current treatment options for radiation-induced fibrosis (RIF) are limited, however, the iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. In this study, we asked whether topical delivery of DFO prior to irradiation could mitigate the chronic effects of irradiation damage in the skin. Methods: CD-1 Nude immunodeficient mice were split into four experimental groups (n=5/group); 1) irradiation with no DFO, 2) irradiation with therapeutic DFO, 3) irradiation with continuous (prophylactic and therapeutic) DFO, and 4) no irradiation and no DFO (control group) (Fig. 1A). DFO was administrated to the mouse scalp using a novel transdermal drug delivery system (TDDS) (Fig. 1B). Prophylactic DFO started 2 weeks prior to irradiation and continued for 6 weeks following irradiation. Therapeutic DFO started 4 weeks after irradiation, when chronic skin fibrosis had developed. Mice scalps were irradiated with a total of 30 Gy. Skin perfusion was monitored with Laser Doppler immediately following irradiation and at 6 weeks after irradiation, at which point the skin was harvested and evaluated histologically for vascularization and fibrosis. Results: Immediately following RT, skin perfusion was significantly improved in mice receiving prophylactic DFO. Six weeks following RT, the mice receiving DFO treatment had the greatest perfusion (Fig. 1C) and increased immunohistological evidence of vascularity (Fig. 1D). Skin fibrosis was significantly reduced in mice receiving DFO, evidenced by decreased dermal thickness, decreased skin collagen content, and more regenerative pattern of collagen fiber networks. The greatest benefits in fibrosis and vascularization were found in mice receiving continuous DFO treatment (Fig. 1Ei-ii). Conclusions: Prophylactic and therapeutic transdermal delivery of deferoxamine improves skin vascularity and reduces the chronic effects of radiation on skin fibrosis, and thus may play an important therapeutic role in patients requiring RT for treatment of their cancer.
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