Nanocarriers for drug delivery to the inner ear: Physicochemical key parameters, biodistribution, safety and efficacy.

Despite the high incidence of inner ear disorders, there are still no dedicated medications on the market. Drugs are currently administered by the intratympanic route, the safest way to maximize drug concentration in the inner ear. Nevertheless, therapeutic doses are ensured for only a few minutes/hours using drug solutions or suspensions. The passage through the middle ear barrier strongly depends on drug physicochemical characteristics. For the past 15 years, drug encapsulation into nanocarriers has been developed to overcome this drawback. Nanocarriers are well known to sustain drug release and protect it from degradation. In this review, in vivo studies are detailed concerning nanocarrier biodistribution, their pathway mechanisms in the inner ear and the resulting drug pharmacokinetics. Key parameters influencing nanocarrier biodistribution are identified and discussed: nanocarrier size, concentration, surface composition and shape. Recent advanced strategies that combine nanocarriers with hydrogels, specific tissue targeting or modification of the round window permeability (cell-penetrating peptide, magnetic delivery) are explored. Most of the nanocarriers appear to be safe for the inner ear and provide a significant efficacy over classic formulations in animal models. However, many challenges remain to be overcome for future clinical applications.