Transtympanic injection of a liposomal gel loaded with N-acetyl-L-cysteine: A relevant strategy to prevent damage induced by cochlear implantation in guinea pigs?

• Published in: International journal of pharmaceutics 2021-07, Vol.604
• Main Authors: Jaudoin, Céline, Carré, Fabienne, Gehrke, Maria, Sogaldi, Audrey, Steinmetz, Vincent, Hue, Nathalie, Cailleau, Catherine, Tourrel, Guillaume, Nguyen, Yann, Ferrary, Evelyne, Agnely, Florence, Bochot, Amélie
• Format: Article
• Language: English
• Subjects: Life Sciences
• ISSN: 0378-5173
• DOI: 10.1016/j.ijpharm.2021.120757

Patients with residual hearing can benefit from cochlear implantation. However, insertion can damage cochlear structures and generate oxidative stress harmful to auditory cells. The antioxidant N-acetyl-L-cysteine (NAC) is a precursor of glutathione (GSH), a powerful endogenous antioxidant. NAC local delivery to the inner ear appeared promising to prevent damage after cochlear implantation in animals. NAC-loaded liposomal gel was specifically 35 designed for transtympanic injection, performed both 3 days before and on the day of surgery. Hearing thresholds were recorded over 30 days in implanted guinea pigs with and without NAC. NAC, GSH, and their degradation products, N,N’-diacetyl-L-cystine (DiNAC) and oxidized glutathione (GSSG) were simultaneously quantified in the perilymph over 15 days in non-implanted guinea pigs. For the first time, endogenous concentrations of GSH and GSSG 40 were determined in the perilymph. Although NAC-loaded liposomal gel sustained NAC release in the perilymph over 15 days, it induced hearing loss in both implanted and non-implanted groups with no perilymphatic GSH increase. Under physiological conditions, NAC appeared poorly stable within liposomes. As DiNAC was quantified at concentrations which were twice as high as NAC in the perilymph, it was hypothesized that DiNAC could be 45 responsible for the adverse effects on hearing.