Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea.

Abstract

Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we use a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by auditory brainstem responses and distortion product otoacoustic emissions. 6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane, or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. There was a dose-dependent increase in fluorescent signal after systemic 6-FAM-ZOL treatment. Local delivery via the round window membrane or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed after either systemic or local 6-FAM-ZOL delivery. These findings establish important preclinical parameters for the treatment of cochlear otosclerosis in humans.