N-acetylcysteine Microparticles Reduce Cisplatin-induced RSC96 Schwann Cell Toxicity.

ABSTRACT

Objectives: Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity. Methods: RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC 50 ). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay. Results: The LC 50 dose of cisplatin was determined to be 3.76 µM (p=2.2 × 10 -16 ). When co-dosed with cisplatin and therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone. Conclusion: RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity. Lay Summary: Cisplatin is a chemotherapeutic agent known to cause balance and hearing problems through damage to the inner ear. This project explored cisplatin injury in a Schwann cell culture model and packaged an antioxidant into microparticles suitable for future drug delivery applications.