Abstract
Medication-induced ototoxicity (MIO) results from treatment regimens such as aminoglycosides and platinum-based drugs, leading to sensory hair cell damage in the inner ear, which is responsible for converting mechanical sound vibrations to the electrical signals for hearing. Our study aims to develop biomaterial-based localized drug delivery systems of therapeutics for the protection of cochlear hair cells. In this study, we developed sodium-thiosulfate (STS)-loaded solid-lipid-nanoparticles (SLNs) and tested them against cisplatin (CisPt)-induced ototoxicity. STS-SLNs were synthesized by the double emulsion evaporation technique followed by characterization using dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), and transmission electron microscopy (TEM). The optimized nanoparticles exhibited optimal physicochemical properties, and stability, including particle size (∼92.3 ± 0.8 nm), polydispersity index (<0.3), zeta potential (-13.23 ± 2.07 mV), and encapsulation efficiency (45.48 ± 5.87). TEM analysis confirmed the STS-SLNs spherical morphology. The STS-SLNs showed sustained release of STS from SLNs with an n value of 0.09 (Fickian diffusion) determined using the Korsmeyer-Peppas model. Cellular uptake studies with House Ear Institute-Organ of Corti (HEI-OC1) cells using Coumarin-6-tagged STS-SLNs showed a maximum uptake at 1 hour via clathrin-mediated endocytosis. The STS-SLNs displayed antioxidant potential in reactive oxygen species (ROS) scavenging assays, and enhanced cell viability in live/dead assays compared to CisPt treatment alone. The molecular signaling pathways were investigated by assessing the expression of STAT3 and Nrf2 pathways in HEI-OC1 cells. STS-SLNs significantly reduced STAT3 and P-STAT3 expression compared to the CisPt-treated group, suggesting a protective effect against CisPt-induced oxidative stress via the STAT3 pathway. STS-SLNs effectively mitigated medication-induced (CisPt) cell damage in auditory cells, highlighting their therapeutic potential for local delivery to the inner ear.