Ferrostatin-1-loaded thermosensitive nanodelivery system for noise-induced hearing loss treatment

Abstract

Hearing loss is one of the most difficult sensory disorders to treat because of complicated anatomical and physiological barriers, which result in systemic administration, making it difficult to achieve effective drug concentrations in the inner ear. We recently found that the ferroptosis inhibitor ferrostatin-1 (Fer-1) can alleviate noise-induced hearing loss but large doses and multiple injections are required. Here, a novel Fer-1-loaded thermosensitive nanodelivery system was constructed by combining the advantages of chitosan (CS) and poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles (NPs). β-Glycerophosphate disodium (β-GP) was added to the gel to make it temperature-sensitive. This thermosensitive nanodelivery system could be injected into the middle ear, change into a semisolid phase, and stick to the middle ear mucosa. In vivo experiments indicate that the gel prolonged retention for at least 7 d, causing little inflammatory response. In addition, the injection of the gel caused a temporary increase in the hearing threshold, but mice returned to normal hearing within 3 d. Finally, we demonstrated that this Fer-1-loaded thermosensitive nanodelivery system could alleviate noise-induced hearing loss (NIHL) by reducing the loss of outer hair cells (OHCs), inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) in a mouse model. Our results demonstrate that intratympanic injection of the Fer-1-loaded thermosensitive nanodelivery system is a safe and effective way to attenuate NIHL, providing a new idea for the treatment of NIHL.