Minimally Invasive Drug Delivery to The Cochlea Through Application of Nanoparticles to The Round Window Membrane

Abstract

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 and block copolymers in polymersomes), were tested as potential tools for drug delivery to the cochlea via application onto the round window membrane in adult mice (strain C3H). One day after round window membrane application, both types of NPs labeled 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 round window membrane was evaluated using disulfiram, a neurotoxic agent, as a model payload. Disulfiram-loaded NP delivery resulted in a significant decrease in the number of spiral ganglion cells starting 2 days postapplication, with associated pronounced hearing loss reaching 20–35 dB 2 weeks postapplication as assessed through auditory brainstem responses. No changes in hair cell morphology and function (as assessed by recording 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 liposome and polymersome NPs are capable of carrying a payload into the inner ear that elicits a biological effect, with consequences measurable by a functional readout.

Keywords::

• cell death
• cochlea
• disulfiram
• hearing thresholds
• liposome
• mice
• nanoparticles
• polymersome
• spiral ganglion

Financial & competing interests disclosure

This study was supported by the European Community 6th Framework Program on Research, Techno logical Development and Demonstration No NMP4-CT- 2006-026556 Nanotechnology-based targeted drug delivery (Nanoear), Grant Agency of the Czech Republic No 309/07/1336, Centrum of Neuroscience, Ministry of Education, Youth and Sports of the Czech Republic (LC554). S Ranjan was additionally supported by the Magnus Ehrnrooth Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that the care and use of animals and all experimental procedures were performed in compliance with the guidelines of the Ethical Committee, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, and followed the principles outlined in the Declaration of Helsinki.

Additional information

Funding

This study was supported by the European Community 6th Framework Program on Research, Techno logical Development and Demonstration No NMP4-CT- 2006-026556 Nanotechnology-based targeted drug delivery (Nanoear), Grant Agency of the Czech Republic No 309/07/1336, Centrum of Neuroscience, Ministry of Education, Youth and Sports of the Czech Republic (LC554). S Ranjan was additionally supported by the Magnus Ehrnrooth Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.