Progress Toward Improved Drug Delivery to the Inner Ear: Methods of Measuring Intracochlear Drug Distribution and Materials-Based Approaches for Controlled Release

Abstract

Hearing loss is the most common sensory deficit and has a profound impact on quality of life. Despite the emergence of promising therapeutic candidates for hearing restoration, the dearth of safe and efficacious methods of delivering drugs to the isolated cochlea and its sensorineural epithelium represents a potential barrier to clinical translation of investigational therapies. To address this, novel drug delivery approaches that aim to improve the spatiotemporal distribution of drug substances along the cochlear axis are being developed and evaluated in preclinical animal models. However, the small volume and anatomic isolation of the cochlea make pharmacokinetic assessment difficult, and existing techniques of measuring drug distribution in the cochlea have limitations. We have developed an approach to measuring drug distribution directly in the cochlea’s sensory epithelium, utilizing targeted fluorescent drug-surrogate substances that can be quantified along the cochlear axis in whole-mount preparations with excellent spatial resolution. We evaluate several fluorescent substances as candidate compounds, which are delivered intracochlearly in vivo by a precise microfluidic injection prior to cochlear dissection, and we compare the distributions with a computational model of drug distribution within the scala tympani compartment. We also measure the distribution of the lead candidate, FM 1-43 FX at multiple timepoints after injection, up to 72 hours. Finally, we propose novel materials-based strategies for injectable polymer vehicles that could be applied as controlled release vehicles for intracochlear drug delivery applications.