Drug Delivery across Barriers to the Middle and Inner Ear

Zhang, Zipei; Li, Xiyu; Zhang, Wei; Kohane, Daniel S.

doi:10.1002/adfm.202008701

Cited by 43 publications

(28 citation statements)

References 124 publications

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“…Compared to systemic infusion, steroids injected via this route have been proposed to be more effective in treating noise- or ototoxin-induced hearing loss and SSNHL while reducing the systemic side-effects ( Xenellis et al, 2016 ; Rybak et al, 2019 ). Drugs can be prepared as simple solutions, or formulated with adjuvants to increase drug permeation across RWM ( Saber, 2010 ; Creber et al, 2019 ; Zhang et al, 2020 ), or encapsulated in nanocarriers or polymer matrices to extend drug release.…”

Section: Pharmacotherapy and Delivery Methodsmentioning

confidence: 99%

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Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities

Liu

Yang

2022

Front. Neurosci.

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Most therapies for treating sensorineural hearing loss are challenged by the delivery across multiple tissue barriers to the hard-to-access anatomical location of the inner ear. In this review, we will provide a recent update on various pharmacotherapy, gene therapy, and cell therapy approaches used in clinical and preclinical studies for the treatment of sensorineural hearing loss and approaches taken to overcome the drug delivery barriers in the ear. Small-molecule drugs for pharmacotherapy can be delivered via systemic or local delivery, where the blood-labyrinth barrier hinders the former and tissue barriers including the tympanic membrane, the round window membrane, and/or the oval window hinder the latter. Meanwhile, gene and cell therapies often require targeted delivery to the cochlea, which is currently achieved via intra-cochlear or intra-labyrinthine injection. To improve the stability of the biomacromolecules during treatment, e.g., RNAs, DNAs, proteins, additional packing vehicles are often required. To address the diverse range of biological barriers involved in inner ear drug delivery, each class of therapy and the intended therapeutic cargoes will be discussed in this review, in the context of delivery routes commonly used, delivery vehicles if required (e.g., viral and non-viral nanocarriers), and other strategies to improve drug permeation and sustained release (e.g., hydrogel, nanocarriers, permeation enhancers, and microfluidic systems). Overall, this review aims to capture the important advancements and key steps in the development of inner ear therapies and delivery strategies over the past two decades for the treatment and prophylaxis of sensorineural hearing loss.

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Section: Pharmacotherapy and Delivery Methodsmentioning

confidence: 99%

“…This procedure is regarded as safe and easy to perform despite a small risk of permanent TM perforation. From thereon, the drug needs to traverse across the RWM or the oval window to access the inner ear ( Zhang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities

Liu

Yang

2022

Front. Neurosci.

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“…Some examples of these effects include (i) increase in the paracellular permeability as a consequence of rearrangement of the intercellular junctions; and (ii) enhancement of molecular permeation across cell membranes and intracellular accumulation as a result of pore formation (sonoporation) or enhanced endocytosis [ 8 , 9 ]. These effects have been exploited to increase the permeability of the BRB [ 10 , 11 , 12 ], the BBB [ 8 , 13 ] (including some clinical trials NCT03119961, NCT04417088, NCT04440358, NCT04528680), the blood-labyrinth barrier in the ear [ 14 , 15 ], and the skin barrier (epidermis) [ 16 , 17 , 18 , 19 ] for a variety of materials (small molecule drugs, antibodies, nanoparticles) that otherwise have limited permeation in these barriers. These studies focused on the importance of a single physicochemical feature of a drug, the molecular weight.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers

et al. 2022

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The combination of ultrasound and microbubbles (USMB) has been applied to enhance drug permeability across tissue barriers. Most studies focused on only one physicochemical aspect (i.e., molecular weight of the delivered molecule). Using an in vitro epithelial (MDCK II) cell barrier, we examined the effects of USMB on the permeability of five molecules varying in molecular weight (182 Da to 20 kDa) and hydrophilicity (LogD at pH 7.4 from 1.5 to highly hydrophilic). Treatment of cells with USMB at increasing ultrasound pressures did not have a significant effect on the permeability of small molecules (molecular weight 259 to 376 Da), despite their differences in hydrophilicity (LogD at pH 7.4 from −3.2 to 1.5). The largest molecules (molecular weight 4 and 20 kDa) showed the highest increase in the epithelial permeability (3-7-fold). Simultaneously, USMB enhanced intracellular accumulation of the same molecules. In the case of the clinically relevant anti- C-X-C Chemokine Receptor Type 4 (CXCR4) nanobody (molecular weight 15 kDa), USMB enhanced paracellular permeability by two-fold and increased binding to retinoblastoma cells by five-fold. Consequently, USMB is a potential tool to improve the efficacy and safety of the delivery of drugs to organs protected by tissue barriers, such as the eye and the brain.

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“…The tympanic membrane (TM), or eardrum, is a barrier that separates the external ear from the middle ear. The outer layer of the TM is a stratum corneum that is structurally similar to that in the skin, and is also impermeable to most molecules [ 1 , 14 ]. There is increasing interest in drug delivery across that barrier, to treat acute and chronic diseases of the middle ear [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…The outer layer of the TM is a stratum corneum that is structurally similar to that in the skin, and is also impermeable to most molecules [ 1 , 14 ]. There is increasing interest in drug delivery across that barrier, to treat acute and chronic diseases of the middle ear [ 14 ]. Otitis media (OM) is the most frequently diagnosed pediatric disease, with more than 12 million physician visits per year in the United States [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Permeation of polyethylene glycols across the tympanic membrane

Zhang

Harty

Zheng

et al. 2021

Giant

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Localized and non-invasive delivery of therapeutics across barriers in the body is challenging. Examples include the flux of drugs across the tympanic membrane (TM) for the treatment of middle ear infections, and across the round window to treat inner ear disease. With the emergence of macromolecular therapies, the question arises as to whether such delivery can be achieved with macromolecules. Here, we have used polyethylene glycols (PEGs) in solutions to investigate macromolecular permeation across the TM in the chinchilla ex vivo . As the molecular weight of PEG increased, flux across the TM decreased, with an exponential relationship between the apparent diffusion coefficient and the molecular weight of the polymers. PEG flux was further decreased if it was released from a poloxamer 407 hydrogel, and lessened with increasing hydrogel concentration. Our results provide a framework for understanding the permeation of macromolecules noninvasively across barriers.

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Drug Delivery across Barriers to the Middle and Inner Ear

Cited by 43 publications

References 124 publications

Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities

Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities

The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers

Permeation of polyethylene glycols across the tympanic membrane

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