Ultrasound Microbubble–Facilitated Inner Ear Delivery of Gold Nanoparticles Involves Transient Disruption of the Tight Junction Barrier in the Round Window Membrane

Abstract

The application of ultrasound microbubbles (USMBs) enhances the permeability of the round window membrane (RWM) and improves drug delivery to the inner ear. In this study, we investigated the efficiency of USMB-aided delivery of chitosan-coated gold nanoparticles (CS-AuNPs) and the mechanism of USMB-mediated enhancement of RMW permeability. We exposed mouse inner ears to USMBs at an intensity of 2 W/cm2 and then filled the tympanic bulla with CS-AuNPs or fluorescein isothiocyanate-decorated CS-AuNPs (FITC-CS-AuNPs). The membrane uptake of FITC-CS-AuNPs and their depth of permeation into the three-layer structure of the RWM, with or without prior USMB treatment, were visualized by z-stack confocal laser scanning microscopy. Ultrastructural changes in the RWM due to USMB-mediated cavitation appeared as sunburn-like peeling and various degrees of depression in the RWM surface, with pore-like openings forming in the outer epithelium. This disruption of the outer epithelium was paralleled by a transient reduction in tight junction (TJ)-associated protein levels in the RWM and an enhanced delivery of FITC-CS-AuNPs into the RWM. Without prior USMB exposure, the treatment with CS-AuNPs also caused a noticeable reduction in TJ proteins of the RWM. Our findings indicated that the combined treatment with USMBs and CS-AuNPs represents a promising and efficient drug and gene delivery vehicle for a trans-RWM approach for inner ear therapy. The outer epithelial layer of the RWM plays a decisive role in controlling the transmembrane transport of substances such as CS-AuNPs following the administration of USMBs. Most importantly, the enhanced permeation of AuNPs involved the transient disruption of the TJ-created paracellular barrier in the outer epithelium of the RWM.

The Effect of Pluronic-Coated Gold Nanoparticles in Hearing Preservation Following Cochlear Implantation-Pilot Study

“…Nevertheless, the possible variations of these parameters make it hard to truly study their toxicity. Initial in vivo studies researching their utility as an inner ear contrast agent observed no effect on the morphology of the hair cells [ 12 , 26 ].…”

“…In recent years, the number of FDA approvals for the use of NPs to treat various auditory diseases has increased [ 11 ]. In a preclinical setting, locally applied chitosan-coated gold nanoparticles (Cs-AuNPs) in the rats’ tympanic bulla did not compromise the animals’ hearing thresholds [ 12 ]. However, AuNPs have not yet been utilized in treating inner ear diseases.…”

Safety and audiological outcome in a case series of tertiary therapy of sudden hearing loss with a biodegradable drug delivery implant for controlled release of dexamethasone to the inner ear

“…Several strategies are under investigation to enhance drug entry into the inner ear through the RWM using magnetic fields ( Du et al, 2013 ; Shapiro et al, 2014 ), ultrasound ( Lin et al, 2021 ), RWM microperforations ( Aksit et al, 2021 ), or nanocarriers ( Jaudoin et al, 2021 ). Approaches to overcome or at least decrease intracochlear basal-apical concentration gradients involve the application of RWM low-frequency micro vibrations ( Flaherty et al, 2021 ) or direct intracochlear drug application ( Chen et al, 2005 ; Hahn et al, 2012 ; Ayoob and Borenstein, 2015 ; Plontke et al, 2017 ; Prenzler et al, 2018 ).…”

Applications of Ultrasound-Mediated Drug Delivery and Gene Therapy

“…The authors explored the efficiency of permeability induction by ultrasound and MBs and aided delivery of nanoparticles in a combined setting. By applying MBinduced sonoporation, the authors achieved transient reversible disruption of the epithelial tight junctions of the round window outer surface membrane, successfully improving site specific drug delivery [79]. Table 2 summarizes clinical trials using ultrasound-mediated therapeutic applications.…”