Inner ear drug delivery for auditory applications. Adv Drug Deliv Rev

Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Advanced drug delivery reviews (Impact Factor: 15.04). 12/2008; 60(15):1583-1599. DOI: 10.1016/j.addr.2008.08.001


Many inner ear disorders cannot be adequately treated by systemic drug delivery. A blood-cochlear barrier exists, similar physiologically to the blood-brain barrier, which limits the concentration and size of molecules able to leave the circulation and gain access to the cells of the inner ear. However, research in novel therapeutics and delivery systems has led to significant progress in the development of local methods of drug delivery to the inner ear. Intratympanic approaches, which deliver therapeutics to the middle ear, rely on permeation through tissue for access to the structures of the inner ear, whereas intracochlear methods are able to directly insert drugs into the inner ear. Innovative drug delivery systems to treat various inner ear ailments such as ototoxicity, sudden sensorineural hearing loss, autoimmune inner ear disease, and for preserving neurons and regenerating sensory cells are being explored.

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    • "9 For the inner ear, although the presence of the blood–labyrinth barrier limits wanted or unwanted systemic diffusion of transfer agents, the cochlea is still considered to be a particularly attractive target organ for the study and potential application of gene therapy involving RNAi. The intratympanic approach, which delivers therapeutics to the middle ear by permeation through the round-window membrane (RWM) for access to the structures of the inner ear, has great potential in both research and clinically.10, 11, 12 The cochlea is a very complicated, enclosed space, and its function is sensitive to small changes in fluid (endolymph and perilymph) volume. "
    W Qi · D Ding · H Zhu · D Lu · Y Wang · J Ding · W Yan · M Jia · Y Guo
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    ABSTRACT: The use of small-interfering RNA (siRNA) has great potential for the development of drugs designed to knock down the expression of damage- or disease-causing genes. However, because of the high molecular weight and negative charge of siRNA, it is restricted from crossing the blood-cochlear barrier, which limits the concentration and size of molecules that are able to gain access to cells of the inner ear. Intratympanic approaches, which deliver siRNA to the middle ear, rely on permeation through the round window for access to the structures of the inner ear. We developed an innovative siRNA delivery recombination protein, TAT double-stranded RNA-binding domains (TAT-DRBDs), which can transfect Cy3-labeled siRNA into cells of the inner ear, including the inner and outer hair cells, crista ampullaris, macula utriculi and macula sacculi, through intact round-window permeation in the chinchilla in vivo, and there were no apparent morphological damages for the time of observation. We also found that Cy3-labeled siRNA could directly enter spiral ganglion neurons and the epithelium of the stria vascularis independently; however, the mechanism is unknown. Therefore, as a non-viral vector, TAT-DRBD is a good candidate for the delivery of double-stranded siRNAs for treating various inner ear ailments and preservation of hearing function.Gene Therapy advance online publication, 10 October 2013; doi:10.1038/gt.2013.49.
    Full-text · Article · Oct 2013 · Gene therapy
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    • "Among the primate order, humans have significantly higher cochlear labyrinth volumes. The average volume of the inner ear fluid is reported to be 80.2 í µí¼‡L [11] [12]. In addition to the small volume of the cochlear fluid, a small change of the cochlear fluid volume can impact drastically the high sensitivity of the hearing function. "
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    ABSTRACT: A simple, sensitive, and specific method for furosemide (FUR) analysis by reverse-phase-HPLC was developed using a Spherisorb C18 ODS 2 column. A chromatographic analysis was carried out using a mobile phase consisting of acetonitrile and 10 mM potassium phosphate buffer solution: 70 : 30 (v/v) at pH 3.85, at a flow rate of 1 mL·min(-1). The UV-detection method was carried out at 233 nm at room temperature. Validation parameters including limit of detection (LOD), limit of quantitation (LOQ), linearity range, precision, accuracy, robustness, and specificity were investigated. Results indicated that the calibration curve was linear (r (2) = 0.9997) in the range of 5.2 to 25,000 ng·mL(-1), with ε value equal to 3.74 × 10(4) L·M(-1) ·cm(-1). The LOD and LOQ were found to be 5.2 and 15.8 ng·mL(-1), respectively. The developed method was found to be accurate (RSD less than 2%), precise, and specific with an intraday and interday RSD range of 1.233-1.509 and 1.615 to 1.963%. The stability of native FUR has also been performed in simulated perilymph and endolymph media (with respective potency in each medium of 99.8 ± 2.3% and 96.68 ± 0.7%, n = 3) after 6 hours. This method may be routinely used for the quantitative analysis of FUR from nanocarriers, USP tablets and release media related to hearing research.
    Full-text · Article · Sep 2013 · Journal of Analytical Methods in Chemistry
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    • "The inner ear represents one of the most challenging target organs for drug delivery, yet the potential clinical benefit to patients and the size of the patient population are immense [1]. Conventional routes such as oral delivery and injections are largely ineffective for several reasons, principally because of the blood–cochlear barrier that blocks most compounds from entering the inner ear from the bloodstream. "
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    ABSTRACT: The inner ear represents one of the most technologically challenging targets for local drug delivery, but its clinical significance is rapidly increasing. The prevalence of sensorineural hearing loss and other auditory diseases, along with balance disorders and tinnitus, has spurred broad efforts to develop therapeutic compounds and regenerative approaches to treat these conditions, necessitating advances in systems capable of targeted and sustained drug delivery. The delicate nature of hearing structures combined with the relative inaccessibility of the cochlea by means of conventional delivery routes together necessitate significant advancements in both the precision and miniaturization of delivery systems, and the nature of the molecular and cellular targets for these therapies suggests that multiple compounds may need to be delivered in a time-sequenced fashion over an extended duration. Here we address the various approaches being developed for inner ear drug delivery, including micropump-based devices, reciprocating systems, and cochlear prosthesis-mediated delivery, concluding with an analysis of emerging challenges and opportunities for the first generation of technologies suitable for human clinical use. These developments represent exciting advances that have the potential to repair and regenerate hearing structures in millions of patients for whom no currently available medical treatments exist, a situation that requires them to function with electronic hearing augmentation devices or to live with severely impaired auditory function. These advances also have the potential for broader clinical applications that share similar requirements and challenges with the inner ear, such as drug delivery to the central nervous system.
    Full-text · Article · Feb 2012 · Advanced drug delivery reviews
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