Radioprotective drug screening in a salivary gland tissue chip

Abstract

Ionizing radiation damage to the salivary glands during head and neck cancer treatment often causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients experience difficulty with eating, speaking, and swallowing and are predisposed to oral infections and tooth decay. While the radioprotective drug amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use and motivate research into discovering alternatives. To address this issue, we have developed a salivary gland mimetic (SGm) tissue chip platform for use in high-content drug discovery. Here, we report on the development and validation of in-chip assays to quantify reduced glutathione and cellular senescence (β-galactosidase) as measures of radiation damage and protection using WR-1065, the active form of amifostine. Following validation, we next tested our assays using other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine, Rapamycin, Ex-Rad, and Palifermin. The validated assays were then used to screen a library of FDA-approved compounds for radioprotection. We screened 438 compounds, obtained 25 hits that were further tested for EC50 values and downselected using information from the PubChem database. Lead compounds were identified that are being tested in preclinical models.