Localized WR-1065 Delivery to Murine Salivary Glands has Radioprotective Effect and Hemodynamic Benefit Over Systemic Administration

Abstract

There are over 50,000 cases of head and neck cancer (HNC) diagnosed each year in the United States. Approximately 75% of these patients will undergo radiation at some point during their treatment, and of those patients over 50% will go on to develop permanent xerostomia. Amifostine is the only FDA approved drug for use in xerostomia radioprophylaxis, but suffers from a narrow therapeutic window and systemic toxicities including severe nausea and hypotension that severely limit its clinical utility. To overcome challenges of systemic administration and potentially increase effectiveness, local delivery via Wharton’s duct of WR-1065 (the active metabolite of Amifostine) was utilized. Our hypothesis is that retroductal delivery of WR-1065 to the murine submandibular gland (SMG) will improve salivary gland function while reducing drug side effects such as hypotension at 90 days following a single xerogenic dose (15.0 Gy) of irradiation. All studies used n = 5 C57BL/6 female mice per treatment group. To assess blood pressure response, anesthetized mice underwent bilateral femoral catheterization and aortic placement of a pressure transducer. Mice received either IV or retroductal doses of Amifostine or WR-1065. Baroreflex was subsequently measured by bolus administration of phenylephrine. For radiation studies, mice received unilateral SMG injection with WR-1065 or saline. A single dose of 15.0 Gy was then delivered to the submandibular glands using a Cs137 irradiator with a slit collimator. Study endpoints include volume of stimulated saliva secretion 90 days post irradiation, SMG histology, and immunohistochemical staining compared to irradiated and nonirradiated control groups. Hemodynamic data show retained baroreflex sensitivity and mean arterial pressure following retrograde WR-1065 injection. Furthermore, mice receiving retrograde WR-1065 show significantly higher volumes of stimulated saliva secretion (61±29 μL) compared to irradiated (14±8 μL) and saline treated controls (19 ±7 μL) at 90 days (p<0.05). Furthermore, no significant difference exists in gland secretion between irradiated WR-1065 treated mice and non-irradiated mice. Preliminary data shows improvement in stimulated saliva secretion and gland histology in WR-1065 retroductally treated mice 90 days post irradiation. Hemodynamic data further supports development of this drug delivery modality for SMG radioprotection, as blood pressure and baroreflex sensitivity are retained following retrograde WR-1065 injection.