Amphiphillic polymer-based enhancers for local drugs delivery to the inner ear

Project Details

Description

Hearing loss is one of the major health concerns worldwide. There are more than 10 million people in the UK with some form of hearing loss, (over 15% of the population). Factors well recognised to cause permanent hearing impairment are aging and exposure to loud noise. Due to aging of population, hearing impairment becomes a burden of the modern society and has detrimental effect on life of individuals.

The problem is, once hearing is affected it cannot be restored. Sensory cells in human cochlea are not replaced when they die. Hence, prevention of hearing loss is still the most viable way of approaching this problem. Efficiency of corticosteroids, antioxidant and apoptosis inhibitors for prevention of hearing losses of different genesis and treatment of tinnitus has been demonstrated by clinical research and practice in recent years.

The inner ear, however, is one of the most challenging target organs for drug delivery. Conventional routes of administration such as oral or parenteral routes are largely ineffective principally because of the blood–perilymph barrier that isolates the inner ear from the blood and maintains the microhomeostasis of the inner ear fluids and cells. Direct injection of drugs into the cochlea for prevention of hearing loss is also not feasible. Human cochlea is situated in the toughest bone of our body and poorly accessible.

Additionally, injection of even small amount of fluid into the cochlea has high risk of complications associated with this route of administration. The round window membrane, a flexible membrane in the bony wall of the cochlea which opens into the middle ear can be used for drug delivery into the cochlea. In this case, drugs are injected into the middle ear and diffuse into the cochlea through the round window membrane. The round window membrane is, however, a complex semi-permeable structure. Clinical research demonstrated that permeability of the round window membrane for specific molecules depends on physical and chemical properties of the molecules. Consequently, application of specific drugs to the round window results in large base-to-apex gradients of these drugs in the cochlea which can result in overdose of the drugs at the base and their insufficient concentrations at cochlear apex. One of the solutions to this problem would be to locally enhance the permeability of the round window to specific drugs while otherwise maintaining its integrity.


The project develops and tests polymer-based enhancers which make the round window membrane and cellular membranes in the cochlea selectively permeable for specific molecules. It has been demonstrated that polymer-bases enhancers significantly improved non-invasive drug delivery to the spinal cord for example. Initially we would like to develop enhancers for delivery of drugs which have been used widely for oto-protection and treatment of noise-induced, age-related and sensorineural hearing losses and tinnitus.

Outcomes of the project will provide an efficient formulation for delivery of drugs into the inner ear. Our results will also be used in further development of advanced formulations for local delivery of peptides (apoptosis inhibitors, neurotrophic factors, antibodies) and plasmids for innovative therapy and gene therapy of the ear, new emerging techniques for treatment of currently untreatable hearing disorders.

Key findings

We developed a self-assembled nanoformulation of methylprednisolone succinatewith carboxylated block copolymer for local glucocorticoid therapy. In vivo experiments were designed for assessment of drug diffusion along the guinea pig cochlea, from the base to apex, without breaking integrity of cochlear bony wall.

All previous experiments for assessing diffusion of drugs along the cochlea have utilized sampling of perilymph along cochlear duct. It is well known, however, that opening of cochlear bony wall for sampling of perilymph significantly increases longitudinal flow of perilymph and causes influx of perilymph into the cochlea through cochlear aqueduct.

To assess the limiting factors during diffusion of drugs through the cochlear round window and along cochlear duct we chose to use salicylate which has a few advantages.

Firstly, salicylate produces clear and specific physiological effect on threshold responses of the auditory nerve to pure tones due to specific block of somatic motility of the outer hair cells. Hence, salicylate diffusion along the cochlear duct can be assessed through monitoring of responses of the auditory nerve without sampling perilymph and introducing associated experimental errors.

Secondly, permeability of the round window membrane to salicylate is high and usage of salicylate helps to avoid errors associated with unknown drug concentration at cochlear base near the inner side of the round window.

Our experiments demonstrated significant frequency dependence of salicylate action and, hence, confirm existence of large base-to apex gradients of the drug along the cochlea. We developed a mathematical model of drug diffusion along cochlear duct and combining it with a model of salicylate action on the auditory nerve thresholds. Validation of the model allowed assessment of the drug gradients along the entire cochlea which cannot be made experimentally.

Extrapolation of the model using geometry of the human cochlea allowed evaluation of the gradients of drugs in cochleae of humans which cannot be done experimentally. Our data support conclusion that it is not feasible to use the round window approach for drug delivery into the cochlea combined with passive diffusion of drugs if therapeutic concentration of drugs at cochlear apex are required.
StatusFinished
Effective start/end date1/07/16 → 1/07/18

Funding

  • Royal Society