The application of ultrasound enhanced local drug delivery with albumin microbubbles in the inner ear system

Direct drug delivery into inner ear can be achieved by three approaches: (1) diffusion of drug through round window; (2) injection of drug through round window; (3) cochleostomy or canalostomy. The latter two approaches are invasive and have the risk of hearing loss and vertigo. Drug diffusion through round window is only the noninvasive approach. However, how to enhance drug diffusion and how to noninvasively promote drug delivery through round window are two issues that need to be investigated. In this study, we target on the practical application of microbubbles (MBs)-ultrasound on increasing the wound window membrane (RWM) permeability for facilitating drug or medication delivering into the inner ear. Using biotin-FITC conjugates (biotin-FITC) as delivered agents and performed on guinea pigs animal models, we showed that the MBs-ultrasound exposure can greatly improve the inner ear system utility of the biotin-FITC delivery via RWM at different kinds of approaches about 3.5 to 38 times compare to that solely soaking biotin-FITC around the RWM for spontaneous diffusion. In addition, sighnificant enhancement of hair cells uptake of gentamicin was demonstrated in animals whose tympanic bullas were soaked with MBs-mixed gentamicin-Texas Red or gentamicin and exposed to ultrasound. Furthermore, the increased permeability of RWM resulted from acoustic cavitation of MBs could also be visualized immediately following ultrasound exposure by using Alexa Fluor 488-conjugated phalloidin as a tracer. Most importantly, such applications were shown without resulting damage to the integrity of RWM or deterioration of the hearing thresholds assessed by auditory brainstem responses, suggesting this MBs-ultrasound not only benefits in developing therapeutic strategies for inner ear diseases, but also help in providing a more precise and well-controlled release for medications passing through the RWM.