Local Drug Delivery for Prevention of Hearing Loss

Abstract

Systemic delivery of therapeutics for targeting the cochlea to prevent or treat hearing loss is challenging. Systemic drugs have to cross the blood-labyrinth barrier (BLB). BLB can significantly prevent effective penetration of drugs in appropriate concentrations to protect against hearing loss caused by inflammation, ototoxic drugs, or acoustic trauma. This obstacle may be obviated by local administration of protective agents. This route can deliver higher concentration of drug compared to systemic application and preclude systemic side effects. Protective agents have been administered by intra-tympanic injection in numerous preclinical studies. Drugs such as steroids, etanercept, D and L-methionine, pifithrin-alpha, adenosine agonists, melatonin, kenpaullone (a cyclin-dependent kinase 2 (CDK2) inhibitor) have been reported to show efficacy against cisplatin ototoxicity in animal models. Several siRNAs have been shown to ameliorate cisplatin ototoxicity when administered by intra-tympanic injection. The application of corticosteroids and a number of other drugs with adjuvants appears to enhance efficacy. Administration of siRNAs to knock down AMPK kinase, liver kinase B1 (LKB1) or G9a in the cochlea have been found to ameliorate noise-induced hearing loss. The local administration of these compounds appears to be effective in protecting the cochlea against damage from cisplatin or noise trauma. Furthermore the intra-tympanic route yields maximum protection in the basal turn of the cochlea which is most vulnerable to cisplatin ototoxicity and noise trauma. There appears to be very little transfer of these agents to the systemic circulation. This would avoid potential side effects including interference with anti-tumor efficacy of cisplatin. Nanotechnology offers strategies to effectively deliver protective agents to the cochlea. This review summarizes the pharmacology of local drug delivery by intra-tympanic injection to prevent hearing loss caused by cisplatin and noise exposure in animals. Future refinements in local protective agents provide exciting prospects for amelioration of hearing loss resulting from cisplatin or noise exposure.

BRAF inhibition protects against hearing loss in mice

“…Seven hundred million people worldwide suffer from varying degrees of hearing loss (1,2). Cisplatin chemotherapy results in hearing loss in 40 to 60% of patients with cancer and impedes the development of language skills in young individuals (3)(4)(5).…”

“…Despite extensive research efforts, to date, there are no Food and Drug Administration (FDA)-approved drugs to protect from noise-, cisplatin-, antibiotic-, or age-related hearing loss. Most candidate compounds currently in preclinical and clinical trials are related to antioxidants, vitamins, inflammation, and glutathione metabolism, such as sodium thiosulfate (STS), N-acetylcysteine, d-methionine, and dexamethasone (1,2,6). For example, STS, a direct inactivator of cisplatin and an antioxidant, was successful at lowering incidence of hearing loss by 48% in children with localized standard-risk hepatoblastoma when administered 6 hours after cisplatin chemotherapy, but lowered survival rate of treated patients with disseminated tumors (7)(8)(9).…”

Evaluating the Efficacy of L-N-acetylcysteine and Dexamethasone in Combination to Provide Otoprotection for Electrode Insertion Trauma

“…Additionally, L-NAC's ROS scavenging properties have consistently been shown to ameliorate cochlear damage due to acoustic-trauma at a concentration of 100 mg/kg/day as well as in manganese-induced ROS in rat pups at a concentration of 20 mM. [17,27,28]. In addition to its direct antioxidant effect, L-NAC provides protection for hair cells against TNF-α induced toxicity in OC explants [29].…”

“…The hair cell death is the result of an increase in stress-induced, pro-apoptotic molecules such as TNF-α, IL-6, IL-1β, mitogen-activated kinase (MAPK), Bax, TNFR1, and Bax/Bcl-2 ratio and caspases [9,16]. These pro-apoptotic molecules can be the result of cellular stress from several sources including inflammation, Fas-receptor activation, DNA damage, or increased endoplasmic reticulum and mitochondrial membrane permeability [17][18][19]. Nevertheless, a significant portion of inflammatory damage is due to ROS generated in key cochlear tissues [8,20].…”

Investigations of the Microvasculature of the Human Macula Utricle in Meniere’s Disease

“…The delivery of local therapeutics to the inner ear is an active field for treating different types of disorders (Nyberg et al, 2019) and clinical trials begin to be implemented for different types of inner ear disorders. The challenge remains as there are several types of barriers in the cochlea and vestibular system (Rybak et al, 2019). Our results and previous studies in animal models on the normal organization of the utricle microvasculature shows that the organization of the BLB is quite similar, suggesting that the microvasculature could be used to deliver therapeutics into the inner ear.…”