Specialty (if any): Head and Neck Surgery

Keywords: hearing loss, cisplatin, atorvastatin

Background:

Cisplatin, the most commonly used platinum-based chemotherapeutic agent, results in irreversible bilateral high-frequency hearing loss in 40-60% of patients and tinnitus in 40% (1), with platinum retention being observed up to 18 months (2). The mechanisms underlying cisplatin-induced ototoxicity are multifaceted, involving DNA crosslinking, formation of DNA adducts, and apoptosis of sensory hair cells (1). Statins have been found to reduce the incidence and severity of hearing loss in adults treated with cisplatin with atorvastatin providing the greatest protection (3). Previous work in our lab demonstrated the mitigation of cisplatin ototoxicity by the antioxidant N-acetylcysteine (NAC) in polycaprolactone (PCL) microparticles; however, the mechanism is nonspecific (4). By utilizing atorvastatin, an HMG-CoA reductase inhibitor, we can explore a more targeted approach.

Objective:

The purpose of this study is to determine if a hydrogel of atorvastatin PDLLA-NH2 microparticles can deliver therapeutic concentrations of atorvastatin to the inner ear via transtympanic injection.

Methods:

RSC96 cell cultures were pre-treated with varying concentrations of atorvastatin before being treated with cisplatin. Cell viability was assessed using CCK-8 assay, and the resulting absorbances were analyzed via two-way ANOVA.

Adjustments were made to our current microparticle protocol to account for the hydrophobicity of atorvastatin and the use of PDLLA-NH2. 

Results:

We discovered a therapeutic range of atorvastatin in cells treated with cisplatin at 0.001 mg/mL and 0.0001 mg/mL (p <0.05). We then successfully encapsulated atorvastatin into PDLLA-NH2 microparticles for use in elution kinetics and retained bioavailability assays.

Conclusions:

We found a statistically significant therapeutic range of atorvastatin that protected the viability of cisplatin-treated RSC96 cells.  We expect to see preserved bioactivity and protection of cell viability at concentrations greater than our initial therapeutic range, given the delayed release of atorvastatin-loaded microparticles.