Active Transport of Peptides Across the Intact Human Tympanic Membrane

Kurabi, Arwa; Noack, V.; Bernhardt, Marlen; Pak, Kwang; Alexander, Thomas S.; Husseman, Jacob; Nguyen, Quyen T.; Harris, Jeffrey P.; Ryan, Allen F.

doi:10.1038/s41598-018-30031-6

Cited by 13 publications

(12 citation statements)

References 33 publications

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“…The level of DNA-tag was quantified in fluid from the lower chamber of the assay described above, by qPCR. Interestingly, we found that transport of peptide linked to DNA occurred at a comparable rate to that of peptide linked to phage (28).…”

Section: Trans-tm Peptides Can Cross the Tm Independent Of Phagementioning

confidence: 76%

“…The diameter of the two chambers was 1.5 mm, small enough that TM fragments could be sealed. Dye was included in the upper chamber to detect leaks, and the device was also tested with WT phage to determine that non-transporting phages were excluded from the lower chamber (28). We first tested trans-TM phage TMT-3 transport across TMs from NTHi-infected MEs of rats as well as from rats with normal MEs.…”

Section: Peptides Mediate Transport Across the Tms Of Other Mammalianmentioning

confidence: 99%

“…We then tested TM fragments from uninfected rat, guinea pig, and rabbit MEs and found that transport for all three species was similar. Finally, we obtained discarded TM fragments from human patients undergoing TM repair and determined that the transport occurred at comparable levels across the human TM as well (28).…”

Section: Peptides Mediate Transport Across the Tms Of Other Mammalianmentioning

confidence: 99%

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Molecular Screening Strategy to Identify a Non-invasive Delivery Mechanism for the Treatment of Middle Ear Disorders

et al. 2020

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Middle ear ailments include a broad range of pathological conditions. Otitis media is the leading middle ear disease of childhood, which incurs significant health care resources in developed countries and, in developing countries, causes significant mortality and morbidity. Recurrent and chronic infections of the middle ear lead to the prolonged presence of inflammatory factors and cellular infiltrates resulting in temporary hearing loss. However, long-term alteration of the middle ear space can pose the risk of permanent damage to the delicate ear structures and cause tissue remodeling. While the etiopathogenesis of middle ear diseases is multifactorial, targeting the biological mechanisms and molecular networks that drive disease development is critical. Yet, a pivotal step in realizing the potential of molecular therapies is the development of methods for local drug delivery, since systemic application risks side effects. Utilizing bacteriophage display in the rat, we discovered rare peptides that are able to transit the intact tympanic membrane from the external canal to the middle ear cavity by an active process. An in vitro assay demonstrated that transport occurs across the tympanic membranes of humans and that the peptides cross the membrane independent of phage. Transport of phage, which is ~900 nm in length, suggests that these peptides could non-invasively deliver drug packages or gene therapy vectors into the middle ear.

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Section: Trans-tm Peptides Can Cross the Tm Independent Of Phagementioning

confidence: 76%

Section: Peptides Mediate Transport Across the Tms Of Other Mammalianmentioning

confidence: 99%

Section: Peptides Mediate Transport Across the Tms Of Other Mammalianmentioning

confidence: 99%

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Molecular Screening Strategy to Identify a Non-invasive Delivery Mechanism for the Treatment of Middle Ear Disorders

et al. 2020

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“…While there are inherent interspecies differences in TM morphology [ 64 ], guinea pigs were used in ex vivo transtympanic permeability studies and chinchillas were used for in vivo otitis media studies. Both are standard accepted animal models for otic studies with similar TM thickness of 10μm in guinea pigs [ 71 ] and 15μm in chinchillas [ 64 ], compared to 35–150μm thickness in humans, dependent on location on the TM [ 9 , 64 , 71 ]. Guinea pigs were chosen for ex vivo studies due to species availability at the primary research site, the University of Pittsburgh, with in vivo chinchilla studies performed at the Medical College of Wisconsin using a well-established disease model for otitis media [ 72 – 74 ].…”

Section: Discussionmentioning

confidence: 99%

Controlled release of ciprofloxacin and ceftriaxone from a single ototopical administration of antibiotic-loaded polymer microspheres and thermoresponsive gel

et al. 2020

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Acute otitis media (AOM) is the main indication for pediatric antibiotic prescriptions, accounting for 25% of prescriptions. While the use of topical drops can minimize the administered dose of antibiotic and adverse systemic effects compared to oral antibiotics, their use has limitations, partially due to low patient compliance, high dosing frequency, and difficulty of administration. Lack of proper treatment can lead to development of chronic OM, which may require invasive interventions. Previous studies have shown that gel-based drug delivery to the ear is possible with intratympanic injection or chemical permeation enhancers (CPEs). However, many patients are reluctant to accept invasive treatments and CPEs have demonstrated toxicity to the tympanic membrane (TM). We developed a novel method of delivering therapeutics to the TM and middle ear using a topical, thermoresponsive gel depot containing antibiotic-loaded poly(lactic-co-glycolic acid) microspheres. Our in vitro and ex vivo results suggest that the sustained presentation can safely allow therapeutically relevant drug concentrations to penetrate the TM to the middle ear for up to 14 days. Animal results indicate sufficient antibiotic released for treatment from topical administration 24h after bacterial inoculation. However, animals treated 72h after inoculation, a more clinically relevant treatment practice, displayed spontaneous clearance of infection as is also often observed in the clinic. Despite this variability in the disease model, data suggest the system can safely treat bacterial infection, with future studies necessary to optimize microsphere formulations for scaled up dosage of antibiotic as well as further investigation of the influence of spontaneous bacterial clearance and of biofilm formation on effectiveness of treatment. To our knowledge, this study represents the first truly topical drug delivery system to the middle ear without the use of CPEs.

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“…[44] Peptides could also cross the uninfected TMs of rats, guinea pigs, rabbits, and humans ex vivo. [45]…”

Section: Peptidesmentioning

confidence: 99%

Drug Delivery across Barriers to the Middle and Inner Ear

Zhang

et al. 2020

Adv Funct Materials

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The prevalence of ear disorders has spurred efforts to develop drug delivery systems to treat these conditions. Here, recent advances in drug delivery systems that access the ear through the tympanic membrane (TM) are reviewed. Such methods are either non-invasive (placed on the surface of the TM), or invasive (placed in the middle ear, ideally on the round window [RW]). The major hurdles to otic drug delivery are identified and highlighted the representative examples of drug delivery systems used for drug delivery across the TM to the middle and (crossing the RW also) inner ear.

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Active Transport of Peptides Across the Intact Human Tympanic Membrane

Cited by 13 publications

References 33 publications

Molecular Screening Strategy to Identify a Non-invasive Delivery Mechanism for the Treatment of Middle Ear Disorders

Molecular Screening Strategy to Identify a Non-invasive Delivery Mechanism for the Treatment of Middle Ear Disorders

Controlled release of ciprofloxacin and ceftriaxone from a single ototopical administration of antibiotic-loaded polymer microspheres and thermoresponsive gel

Drug Delivery across Barriers to the Middle and Inner Ear

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