Deferoxamine to Minimize Fibrosis During Radiation Therapy

Abstract

Significance: By 2030, there will be >4 million radiation-treated cancer survivors living in the United States. Irradiation triggers inflammation, fibroblast activation, and extracellular matrix deposition in addition to reactive oxygen species generation, leading to a chronic inflammatory response. Radiation-induced fibrosis (RIF) is a progressive pathology resulting in skin pigmentation, reduced elasticity, ulceration and dermal thickening, cosmetic deformity, pain, and the need for reconstructive surgery. Recent Advances: Deferoxamine (DFO) is a U.S. Food and Drug Administration (FDA)-approved iron chelator for blood dyscrasia management, which has been found to be proangiogenic, to decrease free radical formation, and reduce cell death. DFO has shown great promise in the treatment and prophylaxis of RIF in preclinical studies. Critical Issues: Systemic DFO has a short half-life and is cumbersome to deliver to patients intravenously. Transdermal DFO delivery is complicated by its high atomic mass and hydrophilicity, preventing stratum corneum penetration. A transdermal drug delivery system was developed to address these challenges, in addition to a strategy for topical administration. Future Directions: DFO has great potential to translate from bench to bedside. An important step in translation of DFO for RIF prophylaxis is to ensure that DFO treatment does not affect the efficacy of radiation therapy. Furthermore, after an initial plethora of studies reporting DFO treatment by intravenous and subcutaneous routes, a significant advantage of recent studies is the success of transdermal and topical delivery. Given the strong foundation of basic scientific research supporting the use of DFO treatment on RIF, clinicians will be closely following the results of the ongoing human studies.

Keywords: iron chelation; irradiation; reactive oxygen species; skin radiation; wound healing.

Derrick C. Wan, MD

Figure 1.

Proposed mechanism of RIF of the skin: normal wound healing (A) versus RIF (B). Normal wound healing (A) is defined by three phases (left to right): inflammation, proliferation, and remodeling. Inflammation results in an immediate platelet response, cytokine and chemoattractant release, and inflammatory immune cells migration. Proliferation results in fibroblast proliferation, transformation of fibroblasts to myofibroblasts, and angiogenesis leading to scar formation by extracellular matrix and collagen deposition. Remodeling leads to degradation of extra collagen and extracellular matrix, resulting in restoration of skin architecture. In the case of RIF (B), after acute radiation injury, there is a prolonged phase of proliferation and a defective phase of remodeling, resulting in extensive deposition of extracellular matrix and collagen, which progresses over many years postradiation. Legend shown in upper right figure panel. Figure adapted with permission from Ejaz et al. and created with Biorender.com. RIF, radiation-induced fibrosis.

Figure 2.

Proposed mechanism of action of DFO. Decreased cellular iron availability after DFO treatment increases VEGF mRNA expression and VEGF protein translation. Iron (Fe²⁺) is a necessary cofactor for PHD, the enzyme responsible for constitutively degrading HIF-1α. By sequestering iron, DFO inactivates PHD resulting in increased HIF-1α accumulation and increased VEGF transcription. DFO prevents iron-catalyzed reactive oxygen stress, while also reducing free radical formation and resultant cell death.^, Figure created with Biorender.com. HIF-1α, hypoxia-inducible factor 1 alpha; DFO, deferoxamine; PHD, prolyl 4-hydroxylase; VEGF, vascular-endothelial growth factor.

Figure 3.

Development of a TDDS for DFO. DFO aggregates with PVP and surfactants to form RMs. RMs are dispersed in the polymer ethyl cellulose. After release from the polymer matrix, the RMs enter the stratum corneum and disintegrate. PVP dissolves and DFO is delivered to the dermis. Figure adapted with permission from Shen et al. and designed using Biorender.com. PVP, polyvinylpyrrolidone; RM, reverse micelle; TDDS, transdermal drug delivery system.

Figure 4.

DFO is effective in prophylaxis of RIF in a mouse model. Laser Doppler analysis and vascularity of scalp skin. Note here “ppx” denotes “prophylaxis.” (A) CD1 Nude mouse with the irradiated area of skin represented by the overlying white box. (B) Representative images of laser Doppler perfusion imaging of treatment and control mouse scalps showing perfusion immediately after radiation (left; irradiated without DFO [top] or with DFO prophylactic treatment [bottom]) and 6 weeks after IR (right). Black/dark blue colors represent lower perfusion and yellow/red colors represent higher perfusion. (C) Quantification of the laser Doppler perfusion index immediately after IR (*p < 0.05, **p < 0.01) and (D) 6 weeks after IR (**p < 0.01). (E) Immunohistochemical staining showing vascular density in all four groups of mice. Endothelial cells were stained with CD31 (PECAM, red) and nuclei were stained with DAPI (blue). Scale bar: 100 μm. (F) Quantification of mean pixels positive for CD31 in all four groups of mice. The skin of nonirradiated mice was significantly more vascularized than the skin of irradiated mice receiving no DFO treatment (****p < 0.0001) and DFO postirradiation only (***p < 0.001). The skin of mice receiving prophylactic DFO treatment was significantly more vascularized than the skin of irradiated mice receiving no DFO (*p < 0.05). Reproduced with permission from Shen et al.