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.

Keywords: acoustic trauma; cisplatin; hearing loss; intra-tympanic injection; noise; ototoxicity.

FIGURE 1

Schematic illustration of barriers within inner ear. Drawing of the cochlea and photomicrograph of a mid-modiolar section of the rat cochlea (stained with Sudan black) demonstrating the various barriers within the inner ear. These include the blood-endolymph barrier (BEB) in the stria vascularis; the blood-perilymph barrier (BPB); and the perilymph-endolymph barrier (PEB) which is formed by Reissner’s membrane (RM). Other abbreviations are: SVA (stria vascularis), SGC (spiral ganglion cells), SV (scala vestibuli), ST (scala tympani) and SM (scala media). Perilymph is contained within SV and ST, and endolymph is present in SM. Adapted from Zou et al. (2016).

FIGURE 2

Schematic diagram illustrating method for intra-tympanic injection. The drug is injected through the tympanic membrane (Heinrich et al., 2016) into the middle ear. It then can penetrate the round window membrane (RW) to enter the inner ear fluids (perilymph) and tissues. Modified from the ACS article https://pubs.acs.org/doi/abs/10.1021%2Facs.jmedchem. 7b01653 with permission.

FIGURE 3

Method for intra-tympanic injection. (A) A syringe with an attached 30 gage needle ½ to 5/8th of an inch in length is directed through the external ear canal to the tympanic membrane of anesthetized animal with an operating microscope. A single puncture is made in the anterior inferior region. The desired solution is slowly injected into the middle ear and the rat is left undisturbed for 15 min with injected ear facing upward (Sheehan et al., 2018). (B) Drawing depicting the injected drug traversing the RWM and entering the cochlea. This figure was modified with permission from the image screenshot at 1:59 of the article https://www.jove.com/video/56564/trans-tympanic-drug-delivery-for-the-treatment-of-ototoxicity.