• Author
    Corinne Negvesky
  • Discovery PI

    Dr. Ashley Kita

  • Project Co-Author

    Amin Mirzaaghasi

  • Abstract Title

    Preclinical Investigation of Atorvastatin-eluting Microparticles for Neuroprotection from Cisplatin Injury

  • Discovery AOC Petal or Dual Degree Program

    Basic, Clinical, & Translational Research

  • Abstract

    Specialty (if any): Head and Neck Surgery

    Keywords: hearing loss, cisplatin, atorvastatin

    Background:

    Cisplatin, a commonly used platinum-based chemotherapeutic agent, results in irreversible bilateral high-frequency hearing loss in 40-60% of patients and tinnitus in 40% (1). 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. Atorvastatin has been found to offer the greatest protection (2). Previous work in our lab demonstrated the mitigation of cisplatin ototoxicity by the antioxidant N-acetylcysteine in polycaprolactone microparticles; however, the mechanism is broad and nonspecific (3). By utilizing atorvastatin, an HMG-CoA reductase inhibitor, we can explore a more targeted approach to otoprotection.

    Objective:

    The purpose of this study is to determine if a hydrogel of atorvastatin microparticles can release therapeutic and bioactive concentrations of atorvastatin in a cell culture model of cisplatin neurotoxicity.

    Methods:

    Rat Schwann Cell (RSC96) cultures were pre-treated with varying concentrations of resuspended and eluted atorvastatin before treatment with cisplatin. Cell viability was assessed, and the resulting absorbances were analyzed via two-way ANOVA.

    Results:

    We found resuspended atorvastatin showed an improvement in cell viability at 10 – 1,000 ng/ml (p<.01). After successfully encapsulating atorvastatin into microparticles, we found protection of viability at 0.0025-1.25 mg/ml when released from water and 0.0025-0.25 mg/ml when released from a thermosensitive hydrogel (p<.01).

    Conclusions:

    We identified a therapeutic range of resuspended atorvastatin (10 – 1,000 ng/ml) and encapsulated atorvastatin in microparticles with retained bioactivity over a similar range of concentrations in our RSC96 cell culture model of cisplatin neurotoxicity.  Further efforts are ongoing to quantify the exact amounts of atorvastatin released over time from our microparticles via HPLC-MS.

    References

    1. Tan, W. J. T., & Vlajkovic, S. M. (2023). Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions. International Journal of Molecular Sciences, 24(22), Article 22. https://doi.org/10.3390/ijms242216545
    2. Fernandez KA, Allen P, Campbell M, et al. Atorvastatin is associated with reduced cisplatin-induced hearing loss. J Clin Invest. 131(1):e142616. doi:10.1172/JCI142616
    3. Fujimoto, C., & Yamasoba, T. (2019). Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review. Antioxidants, 8(4), 109.https://doi.org/10.3390/antiox8040109
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