Identifying Pathogenic Contributors of Radiodermatitis Ameliorated by Smad7-Based Targeting in Canine and Mouse Models.

Abstract

Acute radiodermatitis is a significant complication of radiation therapy (RT) treatment without effective therapy. This study aimed to establish a canine radiodermatitis model and explore a therapeutic intervention to treat radiodermatitis. We developed a canine radiodermatitis model using hypofractionated RT regimens and evaluated the therapeutic potential of topical Tat-PYC-Smad7, a Smad7-based biologic targeting transforming growth factor β and nuclear factor κB signaling pathways. Skin biopsies were collected before RT, after radiodermatitis onset, and posttreatment for histopathology, immunostaining, and RNA sequencing. An enzyme-linked immunosorbent assay was used to assess systemic absorption and antidrug antibody responses. We also examined radiodermatitis in K5.Smad7 transgenic mice, which overexpress Smad7 in the epidermis. Wild-type and K5.Smad7 mice underwent skin irradiation, and radiation-induced dermatitis was monitored and analyzed by histopathology and immunostaining. Hypofractionated RT using doses of 25 to 40 Gy in 5 fractions with 6 MV X-ray intensity modulated RT or 42 to 48 Gy in 10 fractions with a 50 kV superficial X-ray system induced radiodermatitis in dogs within 2 weeks post-RT. Tat-PYC-Smad7 treatment significantly reduced radiodermatitis severity, effectively penetrating keratinocytes and stromal cells without systemic absorption or antidrug antibody formation. RNA sequencing and immunostaining showed reduced DNA damage, neutrophil infiltration, and fibrotic response in treated lesions, with inhibited transforming growth factor β, nuclear factor κB, and JAK/STAT3 signaling. Consistently, K5.Smad7 mice exhibited accelerated radiodermatitis recovery with reduced inflammation and fibrotic response and improved DNA repair compared with wild-type mice. Our study demonstrates that the newly developed radiodermatitis canine model is a valuable tool for studying molecular mechanisms and therapeutic interventions for radiodermatitis. Topical application of Tat-PYC-Smad7 mitigates radiodermatitis by targeting critical pathogenic pathways while minimizing systemic side effects. Similar findings in K5.Smad7 mice suggest that the therapeutic effects of Tat-PYC-Smad7 largely represent the functions of the Smad7 protein.