Minimally invasive drug delivery to the cochlea through application of nanoparticles to the round window membrane

Direct drug delivery to the cochlea is associated with the risk of irreversible damage to the ear. In this study liposome and polymersome nanoparticles (NPs), both formed from amphiphilic molecules (lipids in liposomes, block copolymers in polymersomes), were tested as potential tools for drug delivery to the cochlea through application onto the round window membrane (RWM) in adult mice (strain C3H). One day after RWM application both types of NPs labelled with fluorescent markers were identified in the spiral ganglion in all cochlear turns without producing any distinct morphological or functional damage to the inner ear. NPs were detected, although to a lesser extent, in the organ of Corti and the lateral wall. The potential of liposome and polymersome NPs as therapeutic delivery systems into the cochlea via the RWM was evaluated using disulfiram, a neurotoxic agent as a model payload. Disulfiram-loaded NP delivery resulted in significant decrease in the number of spiral ganglion cells starting two days post-application, with associated pronounced hearing loss reaching 20-35 dB two weeks post-application as assessed through auditory brainstem responses. No changes in hair cell morphology and function (as assessed by recording of otoacoustic emissions) were detected after disulfiram-loaded NP application. No effects were observed in controls where solution of free disulfiram was similarly administered. The results demonstrate that polymersome and liposome NPs are capable of carrying a payload into the inner ear that elicits a biological effect, with consequences measurable by a functional readout