Glycyrrhizic acid and its carrier-free micellar formulation: Unraveling the potential for enhanced oral prevention of hearing loss

Hearing loss, a global health concern, significantly impacts patients with delayed language development, impaired neurocognitive function, and severe social problems. The main cause is the cochlear hair cell damage induced by oxidative stress and inflammation from ototoxic drugs, noise exposure or diabetes. Glycyrrhizic acid (GA), derived from edible herb licorice, is widely utilized in traditional Chinese medicine and clinical treatments for liver diseases. However, its potential in preventing hearing loss remains largely unexplored. Herein, we propose GA as a novel otoprotective agent and demonstrate its capability to prevent hearing loss. Our results show that GA effectively reduces oxidative stress and inflammation induced by cisplatin, aminoglycosides, or even noise and diabetes, thereby protecting cochlear hair cells. In hearing loss models, two commonly used administration methods were compared, with tympanic injection providing better protective effects than oral administration of GA. To enhance oral bioavailability, GA is employed as both the medicine and excipient, and formulated into micelles with curcumin, another extensively used bioactive compound. Interestingly, formulation parameters such as feeding ratio and temperature have little impact on micelle size but significantly affect the drug loading efficiency. The carrier-free strategy can achieve a high drug loading capacity and significantly increase the drug concentration in blood, offering improved preventive efficacy. Notably, the micelles also exhibit protection on kidneys and liver, and do not compromise the antitumor activity of cisplatin. Therefore, GA holds promise as an otoprotective candidate, with potential clinical applications for oral prophylaxis of hearing loss using the micellar formulation.