Ultrasound Microbubbles Enhance the Efficacy of Insulin-Like Growth Factor-1 Therapy for the Treatment of Noise-Induced Hearing Loss.

Yi-Chun Lin,Yuan-Yung Lin,Ying-Liang Chou,Ai-Ho Liao,Hsin-Chien Chen,Chia-Lien Hung,Chih-Hung Wang,Chao-Yin Kuo,Cheng-Ping Shih

doi:10.3390/molecules26123626

Abstract

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.

Highlights

The inner ear is a vulnerable sensory organ responsible for hearing and balance
To determine whether the application of ultrasound-irradiated MBs facilitates the delivery of insulin-like growth factor 1 (IGF-1) to the inner ear, the IGF-1 concentration in the inner ear perilymph in the ultrasound microbubble (USM) group, which received local application of rhIGF-1 to the round window membrane (RWM) following Ultrasound microbubbles (USMBs)
These findings demonstrated that USMBs can facilitate IGFgroups 72 h after treatment

Summary

Introduction

The inner ear is a vulnerable sensory organ responsible for hearing and balance. In adult mammals, since cochlear hair cells have no capacity for regeneration, damage to the cochlea often results in permanent hearing loss [1]. Intratympanic delivery of drugs is commonly utilized to treat several hearing and vestibular diseases [2] Drug delivery via this approach is mainly dependent on drug diffusion through the round window membrane (RWM), an interface between the middle ear and inner ear. USMBs promote the local delivery of dexamethasone, a commonly administered drug, to the inner ear and enhance its anti-inflammatory effect on the cochlea [10]. This suggests that USMBs can be used in combination with intratympanic steroid injections as a treatment modality to improve the outcomes of inner ear diseases. Our previous results reveal that enhanced permeability of the RWM to biotin-FITC can be sustained for approximately 72 h after

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