Skip to main content
SpringerLink
Log in

Innovative pharmaceutical approaches for the management of inner ear disorders

  • Review Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

The sense of hearing is essential for permitting human beings to interact with the environment, and its dysfunctions can strongly impact on the quality of life. In this context, the cochlea plays a fundamental role in the transformation of the airborne sound waves into electrical signals, which can be processed by the brain. However, several diseases and external stimuli (e.g., noise, drugs) can damage the sensorineural structures of cochlea, inducing progressive hearing dysfunctions until deafness. In clinical practice, the current pharmacological approaches to treat cochlear diseases are based on the almost exclusive use of systemic steroids. In the last decades, the efficacy of novel therapeutic molecules has been proven, taking advantage from a better comprehension of the pathological mechanisms underlying many cochlear diseases. In addition, the feasibility of intratympanic administration of drugs also permitted to overcome the pharmacokinetic limitations of the systemic drug administration, opening new frontiers in drug delivery to cochlea. Several innovative drug delivery systems, such as in situ gelling systems or nanocarriers, were designed, and their efficacy has been proven in vitro and in vivo in cochlear models. The current review aims to describe the art of state in the cochlear drug delivery, highlighting lights and shadows and discussing the most critical aspects still pending in the field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Yorgason JG, Fayad JN, Kalinec F. Understanding drug ototoxicity: molecular insights for prevention and clinical management. Expert Opin Drug Saf. 2006;5(3):383–99.

    Article  CAS  PubMed  Google Scholar 

  2. Vassiliou A, Vlastarakos PV, Maragoudakis P, Candiloros D, Nikolopoulos TP. Meniere’s disease: still a mystery disease with difficult differential diagnosis. Ann Indian Acad Neurol. 2011;14(1):12–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wei BP, Stathopoulos D, O'Leary S. Steroids for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev. 2013; doi:10.1002/14651858.CD003998.pub3.

    Google Scholar 

  4. Salt AN, Plontke SK. Local inner-ear drug delivery and pharmacokinetics. Drug Discov Today. 2005;10(19):1299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. El Kechai N, Agnely F, Mamelle E, Nguyen Y, Ferrary E, Bochot A. Recent advances in local drug delivery to the inner ear. Int J Pharm. 2015;494:83–101.

    Article  CAS  PubMed  Google Scholar 

  6. Nguyen K, Kempfle JS, Jung DH, McKenna CE. Recent advances in therapeutic and drug delivery for the treatment of inner ear disease: a patent review (2011-2015). Exp Op Therap Patent. 2017;27(2):191–202.

    Article  CAS  Google Scholar 

  7. Litovsky RY, Gordon K. Bilateral cochlear implants in children: effects of auditory experience and deprivation on auditory perception. Hear Res. 2016;338:76–87.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nguyen S, Cloutier F, Philippon D, Côté M, Bussières R, Backous DD. Outcomes review of modern hearing preservation technique in cochlear implant. Auris Nasus Larynx. 2016;43(5):485–8.

    Article  PubMed  Google Scholar 

  9. Lim DJ. Structure and function of the tympanic membrane: a review. Acta Otorhinolaryngol Belg. 1995;49(2):101–15.

    CAS  PubMed  Google Scholar 

  10. Williams C. Hearing restoration: Graeme Clark, Ingeborg Hochmair, and Blake Wilson receive the 2013 Lasker~DeBakey Clinical Medical Research Award. J Clin Invest. 2013;123(10):4102–6.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Igarashi M, Ohashi K, Ishii M. Morphometric comparison of endolympatic and perilymphatic spaces in human temporal bones. Acta Otolaryngol. 1986;101(3–4):161–4.

    Article  CAS  PubMed  Google Scholar 

  12. Zdebik AA, Wangemann P, Jentsch T. Potassium ion movement in the inner ear: insights from genetic disease and mouse models. Physiology. 2009;24:307–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Misrahy GA, Spradley JF, Beran AV, Garwood VP. Permeability of cochlear partitions: comparison with blood-brain barrier. Acta Otolaryngol. 1960;52:525–34.

    Article  CAS  PubMed  Google Scholar 

  14. Principi N, Marchisio P, Rosazza C, Sciarrabba CS, Esposito S. Acute otitis media with spontaneous tympanic membrane perforation. Eur J Clin Microbiol Infect Dis. 2017;36(1):11–8.

    Article  CAS  PubMed  Google Scholar 

  15. Ryan AF, Harris JP, Keithley EM. Immune-mediated hearing loss: basic mechanisms and options for therapy. Acta Otolaryngol Suppl. 2002;548:38–43.

    Article  Google Scholar 

  16. Ruckenstein MJ. Autoimmune inner ear disease. Curr Opin Otolaryngol Head Neck Surg. 2004;12(5):426–30.

    Article  PubMed  Google Scholar 

  17. Yamane H, Nakai Y, Takayama M, Iguchi H, Nakagawa T, Kojima A. Appearance of free radicals in the guinea pig inner ear after noise-induced acoustic trauma. Eur Arch Otorhinolaryngol. 1995;252(8):504–8.

    Article  CAS  PubMed  Google Scholar 

  18. Ishida A, Sugisawa T, Yamamura K. Effects of high-frequency sound on the guinea pig cochlea. Electrophysiological study using cochlear microphonics, action and endocochlear potential. ORL J Otorhinolaryngol Relat Spec. 1993;55(6):332–6.

    Article  CAS  PubMed  Google Scholar 

  19. Bhandare N, Antonelli PJ, Morris CG, Malayapa RS, Mendenhall WM. Ototoxicity after radiotherapy for head and neck tumors. Int J Radiat Oncol Biol Phys. 2007;67(2):469–79.

    Article  PubMed  Google Scholar 

  20. Paparella MM, Goycoolea MV, Meyerhoff WL. Inner ear pathology and otitis media. A review. Ann Otol Rhinol Laryngol Suppl. 1980;89(3 Pt 2):249–53.

    Article  CAS  PubMed  Google Scholar 

  21. Goycoolea MV. Clinical aspects of round window membrane permeability under normal and pathological conditions. Acta Otolaryngol. 2001;121(4):437–47.

    Article  CAS  PubMed  Google Scholar 

  22. Temple MD, Perrone GG, Dawes IW. Complex cellular responses to reactive oxygen species. Trends Cell Biol. 2005;15(6):319–26.

    Article  CAS  PubMed  Google Scholar 

  23. Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res. 2007;226(1–2):157–67.

    Article  CAS  PubMed  Google Scholar 

  24. Ding D, Stracher A, Salvi RJ. Leupeptin protects cochlear and vestibular hair cells from gentamicin ototoxicity. Hear Res. 2002;164(1–2):115–26.

    Article  CAS  PubMed  Google Scholar 

  25. Jacono AA, Hu B, Kopke RD, Henderson D, Van De Water TR, Steinman HM. Changes in cochlear antioxidant enzyme activity after sound conditioning and noise exposure in the chinchilla. Hear Res. 1998;117(1–2):31–8.

    Article  CAS  PubMed  Google Scholar 

  26. Yamane H, Nakai Y, Konishi K, Sakamoto H, Matsuda Y, Iguchi H. Strial circulation impairment due to acoustic trauma. Acta Otolaryngol. 1991;111(1):85–93.

    Article  CAS  PubMed  Google Scholar 

  27. Ruby B, McBain CJ. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 2001;24:517–26.

    Article  Google Scholar 

  28. Bing D, Lee SC, Campanelli D, Xiong H, Matsumoto M, Panford-Walsh R, et al. Cochlear NMDA receptors as therapeutic target of noise-induced tinnitus. Cell Physiol Biochem. 2015;35:1905–23.

    Article  CAS  PubMed  Google Scholar 

  29. Goutman JD, Elgoyhen AB, Gomez-Casati ME. Cochlear hair cells: the sound-sensing machines. FEBS Lett. 2015;589(22):3354–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Darbon P, Wright DJ, Evans MG. Conductance properties of the acetylcholine receptor current of Guinea pig outer hair cells. J Assoc Res Otolaryngol. 2011;12(1):59–70.

    Article  PubMed  Google Scholar 

  31. Plazas PV, Savino J, Kracun S, Gomez-Casati ME, Katz E, Parsons CG, et al. Inhibition of the alpha9alpha10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-D-aspartate receptors. Eur J Pharmacol. 2007;566(1–3):11–9.

    Article  CAS  PubMed  Google Scholar 

  32. Eggermont JJ. Tinnitus: neurobiological substrates. Drug Discov Today. 2005;10(19):1283–90.

    Article  PubMed  Google Scholar 

  33. Salt AN, Plontke SK. Endolymphatic hydrops: pathophysiology and experimental models. Otolaryngol Clin N Am. 2010;43(5):971–83.

    Article  Google Scholar 

  34. Degerman E, In't Zandt R, Palbrink AK, Magnusson M. Vasopressin induces endolymphatic hydrops in mouse inner ear, as evaluated with repeated 9.4 T MRI. Hear Res. 2015;330:119–24.

    Article  CAS  PubMed  Google Scholar 

  35. Nishioka R, Takeda T, Kakigi A, Okada T, Takebayashi S, Taguchi D, et al. Expression of aquaporins and vasopressin type 2 receptor in the stria vascularis of the cochlea. Hear Res. 2010;260(1–2):11–9.

    Article  CAS  PubMed  Google Scholar 

  36. Maekawa C, Kitahara T, Kizawa K, Okazaki S, Kamakura T, Horii A, et al. Expression and translocation of aquaporin-2 in the endolymphatic sac in patients with Meniere’s disease. J Neuroendocrinol. 2010;22(11):1157–64.

    Article  CAS  PubMed  Google Scholar 

  37. Plontke SK, Hartsock JJ, Gill RM, Salt AN. Intracochlear drug injections through the round window membrane: measures to improve drug retention. Audiol Neurootol. 2016;21(2):72–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zou J, Ostrovsky S, Israel LL, Feng H, Kettunen MI, Lellouche JPM, et al. Efficient penetration of ceric ammonium nitrate oxidant-stabilized gamma-maghemite nanoparticles through the oval and round windows into the rat inner ear as demonstrated by MRI. J Biomed Mater Res B Appl Biomater. 2016; doi:10.1002/jbm.b.33719.

    PubMed  Google Scholar 

  39. Smith BM, Myers MG. The penetration of gentamicin and neomycin into perilymph across the round window membrane. Otolaryngol Head Neck Surg. 1979;87(6):888–91.

    Article  CAS  PubMed  Google Scholar 

  40. Youm I, Musazzi UM, Gratton MA, Murowchick JB, Youan BBC. Label-free ferrocene-loaded nanocarrier engineering for in vivo cochlear drug delivery and imaging. J Pharm Sci. 2016;105(10):3162–71.

    Article  CAS  PubMed  Google Scholar 

  41. Lundman L, Juhn SK, Bagger-Sjoback D, Svanborg C. Permeability of the normal round window membrane to Haemophilus influenzae type b endotoxin. Acta Otolaryngol. 1992;112(3):524–9.

    Article  CAS  PubMed  Google Scholar 

  42. Goycoolea MV, Muchow D, Schachern P. Experimental studies on round window structure: function and permeability. Laryngoscope. 1988;98:1–20.

    Article  CAS  PubMed  Google Scholar 

  43. Zou J, Sood R, Ranjan S, Poe D, Ramadan UA, Pyykko I, et al. Size-dependent passage of liposome nanocarriers with preserved post-transport integrity across the middle-inner ear barriers in rats. Otol Neurotol. 2012;33(4):666–73.

    Article  PubMed  Google Scholar 

  44. Plontke SK, Salt AN. Simulation of application strategies for local drug delivery to the inner ear. ORL J Otorhinolaryngol Relat Spec. 2006;68(6):386–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Phillips JS, Westerberg B. Intratympanic steroids for Ménière’s disease or syndrome. Cochrane Database Syst Rev. 2011; doi:10.1002/14651858.CD008514.pub2.

    Google Scholar 

  46. Liu B, Zhang S, Leng Y, Zhou R, Liu J, Kong W. Intratympanic injection in delayed endolymphatic hydrops. Acta Otolaryngol. 2015;135(10):1016–21.

    Article  PubMed  CAS  Google Scholar 

  47. Albu S, Chirtes F. Intratympanic dexamethasone plus melatonin versus melatonin only in the treatment of unilateral acute idiopathic tinnitus. Am J Otolaryngol. 2014;35(5):617–22.

    Article  PubMed  Google Scholar 

  48. Chandrasekhar SS. In reference to intratympanic dexamethasone injection for refractory tinnitus: Prospective placebo-controlled study. Laryngoscope. 2014; doi:10.1002/lary.24438.

    PubMed  Google Scholar 

  49. El Sabbagh NG, Sewitch MJ, Bezdjian A, Daniel SJ. Intratympanic dexamethasone in sudden sensorineural hearing loss: a systematic review and meta-analysis. Laryngoscope. 2016; doi:10.1002/lary.26394.

    PubMed  Google Scholar 

  50. Kim SK, Im GJ, An YS, Lee SH, Jung HH, Park SY. The effects of the antioxidant alpha-tocopherol succinate on cisplatin-induced ototoxicity in HEI-OC1 auditory cells. Int J Pediatr Otorhinolaryngol. 2016;86:9–14.

    Article  PubMed  Google Scholar 

  51. So HS, Park C, Kim HJ, Lee JH, Park SY, Lee ZW, et al. Protective effect of T-type calcium channel blocker flunarizine on cisplatin-induced death of auditory cells. Hear Res. 2005;204(1–2):127–39.

    Article  CAS  PubMed  Google Scholar 

  52. Du X, Li W, Gao X, West MB, Saltzman WM, Cheng CJ, et al. Regeneration of mammalian cochlear and vestibular hair cells through Hes1/Hes5 modulation with siRNA. Hear Res. 2013;304:91–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wu CY, Lee HJ, Liu CF, Korivi M, Chen HH, Chan MH. Protective role of L-ascorbic acid, N-acetylcysteine and apocynin on neomycin-induced hair cell loss in zebrafish. J Appl Toxicol. 2015;35(3):273–9.

    Article  CAS  PubMed  Google Scholar 

  54. Bas E, Van De Water TR, Lumbreras V, Rajguru S, Goss G, Hare JM, Goldstein BJ. Adult human nasal mesenchymal-like stem cells restore cochlear spiral ganglion neurons after experimental lesion. Stem Cells Dev. 2014;23:502–14.

    Article  CAS  PubMed  Google Scholar 

  55. Feghali JG, Liu W, Van De Water TR. L-n-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope. 2001;111(7):1147–55.

    Article  CAS  PubMed  Google Scholar 

  56. Youn CK, Jo ER, Sim JH, Cho SI. Peanut sprout extract attenuates cisplatin-induced ototoxicity by induction of the Akt/Nrf2-mediated redox pathway. Int J Pediatr Otorhinolaryngol. 2017;92:61–6.

    Article  PubMed  Google Scholar 

  57. Bonabi S, Caelers A, Monge A, Huber A, Bodmer D. Resveratrol protects auditory hair cells from gentamicin toxicity. Ear Nose Throat J. 2008;87(10):570–3.

    PubMed  Google Scholar 

  58. Neuwelt EA, Brummett RE, Remsen LG, Kroll RA, Pagel MA, McCormick CI, et al. In vitro and animal studies of sodium thiosulfate as a potential chemoprotectant against carboplatin-induced ototoxicity. Cancer Res. 1996;56(4):706–9.

    CAS  PubMed  Google Scholar 

  59. Glueckert R, Pritz CO, Roy S, Dudas J, Schrott-Fischer A. Nanoparticle mediated drug delivery of rolipram to tyrosine kinase B positive cells in the inner ear with targeting peptides and agonistic antibodies. Front Aging Neurosci. 2015; doi:10.3389/fnagi.2015.00071.

    PubMed  PubMed Central  Google Scholar 

  60. Astolfi L, Simoni E, Valente F, Ghiselli S, Hatzopoulos S, Chicca M, et al. Coenzyme Q10 plus multivitamin treatment prevents cisplatin ototoxicity in rats. PLoS One. 2016;11(9):e0162106.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Sun C, Wang X, Chen D, Lin X, Yu D, Wu H. Dexamethasone loaded nanoparticles exert protective effects against cisplatin-induced hearing loss by systemic administration. Neurosci Lett. 2016;619:142–8.

    Article  CAS  PubMed  Google Scholar 

  62. Sun C, Wang X, Zheng Z, Chen D, Shi F, Yu D, et al. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration. Int J Nanomedicine. 2015;10:3567–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Toplu Y, Sapmaz E, Parlakpinar H, Kelles M, Kalcioglu MT, Tanbek K, et al. The effect of dexpanthenol on ototoxicity induced by cisplatin. Clin Exp Otorhinolaryngol. 2016;9(1):14–20.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Ekborn A, Laurell G, Johnstrom P, Wallin I, Eksborg S, Ehrsson H. D-Methionine and cisplatin ototoxicity in the guinea pig: D-methionine influences cisplatin pharmacokinetics. Hear Res. 2002;165(1–2):53–61.

    Article  CAS  PubMed  Google Scholar 

  65. Uzun L, Kokten N, Cam OH, Tayyar Kalcioglu M, Birol Ugur M, Tekin M, et al. The effect of garlic derivatives (S-allylmercaptocysteine, diallyl disulfide, and S-allylcysteine) on gentamicin induced ototoxicity: an experimental study. Clin Exp Otorhinolaryngol. 2016;9(4):309–13.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Dias MA, Sampaio AL, Venosa AR, Meneses Ede A, Oliveira CA. The chemopreventive effect of Ginkgo biloba extract 761 against cisplatin ototoxicity: a pilot study Int Tinnitus J 2015; 19(2):12–9.

  67. Inaoka T, Nakagawa T, Kikkawa YS, Tabata Y, Ono K, Yoshida M, et al. Local application of hepatocyte growth factor using gelatin hydrogels attenuates noise-induced hearing loss in guinea pigs. Acta Otolaryngol. 2009;129(4):453–7.

    Article  CAS  PubMed  Google Scholar 

  68. Iwai K, Nakagawa T, Endo T, Matsuoka Y, Kita T, Kim TS, et al. Cochlear protection by local insulin-like growth factor-1 application using biodegradable hydrogel. Laryngoscope. 2006;116(4):529–33.

    Article  CAS  PubMed  Google Scholar 

  69. Fujiwara T, Hato N, Nakagawa T, Tabata Y, Yoshida T, Komobuchi H, et al. Insulin-like growth factor I treatment via hydrogels rescues cochlear hair cells from ischemic injury. Neuroreport. 2008;19(16):1585–8.

    Article  CAS  PubMed  Google Scholar 

  70. Demir MG, Altintoprak N, Aydin S, Kosemihal E, Basak K. Effect of transtympanic injection of melatonin on cisplatin-induced ototoxicity. J Int Adv Otol. 2015;11(3):202–6.

    Article  PubMed  Google Scholar 

  71. Choe WT, Chinosornvatana N, Chang KW. Prevention of cisplatin ototoxicity using transtympanic N-acetylcysteine and lactate. Otol Neuroto. 2004;25(6):910–5.

    Article  Google Scholar 

  72. Suzuki J, Corfas G, Liberman MC. Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure. Sci Rep. 2016; doi:10.1038/srep24907.

    Google Scholar 

  73. Mukherjea D, Jajoo S, Kaur T, Sheehan KE, Ramkumar V, Rybak LP. Transtympanic administration of short interfering (si)RNA for the NOX3 isoform of NADPH oxidase protects against cisplatin-induced hearing loss in the rat. Antioxid Redox Signal. 2010;13(5):589–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bekmez Bilmez ZE, Aydin S, Sanli A, Altintoprak N, Demir MG, Atalay Erdogan B, et al. Oxytocin as a protective agent in cisplatin-induced ototoxicity. Cancer Chemother Pharmacol. 2016;77(4):875–9.

    Article  CAS  PubMed  Google Scholar 

  75. Benkafadar N, Menardo J, Bourien J, Nouvian R, François F, Decaudin D, et al. Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy. EMBO Mol Med. 2017;9(1):7–26.

    Article  CAS  PubMed  Google Scholar 

  76. Simsek G, Tokgoz SA, Vuralkan E, Caliskan M, Besalti O, Akin I. Protective effects of resveratrol on cisplatin-dependent inner-ear damage in rats. Eur Arch Otorhinolaryngol. 2012;270(6):1789–93.

    Article  PubMed  Google Scholar 

  77. Seidman M, Babu S, Tang W, Naem E, Quirk WS. Effects of resveratrol on acoustic trauma. Otolaryngol Head Neck Surg. 2003;129(5):463–70.

    Article  PubMed  Google Scholar 

  78. Erdem T, Bayindir T, Filiz A, Iraz M, Selimoglu E. The effect of resveratrol on the prevention of cisplatin ototoxicity. Eur Arch Otorhinolaryngol. 2011;269(10):2185–8.

    Article  PubMed  Google Scholar 

  79. Doolittle ND, Muldoon LL, Brummett RE, Tyson RM, Lacy C, Bubalo JS, et al. Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res. 2001;7(3):493–500.

    CAS  PubMed  Google Scholar 

  80. Dickey DT, Wu YJ, Muldoon LL, Neuwelt EA. Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. The J Pharmacol Exp Ther. 2005;314(3):1052–8.

    Article  CAS  PubMed  Google Scholar 

  81. Barboza LCM, Lezirovitz K, Zanatta DB, Strauss BE, Mingroni-Netto RC, Oiticica J, et al. Transplantation and survival of mouse inner ear progenitor/stem cells in organ of Corti after cochleostomy of hearing-impaired guinea pigs: preliminary results. Braz J Med Biol Res. 2016; doi:10.1590/1414-431X20155064.

    PubMed  PubMed Central  Google Scholar 

  82. Chien WW, Isgrig K, Roy S, Belyantseva IA, Drummond MC, May LA, et al. Gene therapy restores hair cell stereocilia morphology in inner ears of deaf whirler mice. Mol Ther. 2016;24:17–25.

    Article  CAS  PubMed  Google Scholar 

  83. Boffi JC, Wedemeyer C, Lipovsek M, Katz E, Calvo DJ, Elgoyhen AB. Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid. Br J Pharmacol. 2013;168:954–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jadali A, Kwan KY. Activation of PI3K signaling prevents aminoglycoside-induced hair cell death in the murine cochlea. Biol Open. 2016;5(6):698–708.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Vlajkovic SM, Lin SCY, Wong ACY, Wackrow B, Thorne PR. Noise-induced changes in expression levels of NADPH oxidases in the cochlea. Hear Res. 2013;304:145–52.

    Article  CAS  PubMed  Google Scholar 

  86. Okano T, Kelley MW. Stem cell therapy for the inner ear: recent advances and future directions. Trends Amplif. 2012;16:4–18.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Koehler KR, Mikosz AM, Molosh AI, Patel D, Hashino E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature. 2013;500:217–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Plontke SK, Mikulec AA, Salt AN. Rapid clearance of methylprednisolone after intratympanic application in humans. Comment on: Bird PA, Begg EJ, Zhang M, et al. Intratympanic versus intravenous delivery of methylprednisolone to cochlear perilymph. Otol Neurotol 2007;28:1124-30. Otol Neurotol. 2008;29(5):732–3.

    Article  PubMed  Google Scholar 

  89. Yu D, Sun C, Zheng Z, Wang X, Chen D, Wu H, et al. Inner ear delivery of dexamethasone using injectable silk-polyethylene glycol (PEG) hydrogel. Int J Pharm. 2016;503(1–2):229–37.

    Article  CAS  PubMed  Google Scholar 

  90. Engleder E, Honeder C, Klobasa J, Wirth M, Arnoldner C, Gabor F. Preclinical evaluation of thermoreversible triamcinolone acetonide hydrogels for drug delivery to the inner ear. Int J Pharm. 2014;471(1–2):297–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Borden RC, Saunders JE, Berryhill WE, Krempl GA, Thompson DM, Queimado L. Hyaluronic acid hydrogel sustains the delivery of dexamethasone across the round window membrane. Audiol Neurootol. 2011;16(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  92. Paulson DP, Abuzeid W, Jiang H, Oe T, O'MalleyBW, Li D. A novel controlled local drug delivery system for inner ear disease. Laryngoscope. 2008;118(4):706–11.

    Article  CAS  PubMed  Google Scholar 

  93. Lajud SA, Han Z, Chi FL, Gu R, Nagda DA, Bezpalko O, et al. A regulated delivery system for inner ear drug application. J Control Release. 2013;166(3):268–76.

    Article  CAS  PubMed  Google Scholar 

  94. Feng L, Ward JA, Li SK, Tolia G, Hao J, Choo DI. Assessment of PLGA–PEG–PLGA copolymer hydrogel for sustained drug delivery in the ear. Curr Drug Delivery. 2014;11:279–86.

    Article  CAS  Google Scholar 

  95. Honeder C, Engleder E, Schopper H, Gabor F, Reznicek G, Wagenblast J, Gstoettner W, Arnoldner C. Sustained release of triamcinolone acetonide from an intratympanically applied hydrogel designed for the delivery of high glucocorticoid doses. Audiol Neurootol. 2014;19:193–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Nayagam BA, Backhouse SS, Cimenkaya C, Shepherd RK. Hydrogel limits stem cell dispersal in the deaf cochlea: implications for cochlear implants. J Neural Eng. 2012; doi:10.1088/1741-2560/9/6/065001.

    PubMed  PubMed Central  Google Scholar 

  97. Hütten M, Dhanasingh A, Hessler R, Stöver T, Esser KH, Möller M, et al. In vitro and in vivo evaluation of a hydrogel reservoir as a continuous drug delivery system for inner ear treatment. PLoS ONE. 2014;9(8):e104564.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Honeder C, Zhu C, Schöpper H, Gausterer JC, Walter M, Landegger LD, et al. Effects of sustained release dexamethasone hydrogels in hearing preservation cochlear implantation. Hear Res. 2016;341:43–9.

    Article  CAS  PubMed  Google Scholar 

  99. Wrzeszcz A, Steffens M, Balster S, Warnecke A, Dittrich B, Lenarz T, et al. Hydrogel coated and dexamethasone releasing cochlear implants: quantification of fibrosis in guinea pigs and evaluation of insertion forces in a human cochlea model. J Biomed Mater Res B Appl Biomater. 2015;103(1):169–78.

    Article  PubMed  CAS  Google Scholar 

  100. Chikar JA, Hendricks JL, Richardson-Burns SM, Raphael Y, Pfingst BE, Martin DC. The use of a dual PEDOT and RGD-functionalized alginate hydrogel coating to provide sustained drug delivery and improved cochlear implant function. Biomaterials. 2012;33(7):1982–90.

    Article  CAS  PubMed  Google Scholar 

  101. Tamura T, Kita T, Nakagawa T, Endo T, Kim TS, Ishihara T et al Drug delivery to the cochlea using PLGA nanoparticles. Laryngoscope 2005;115(11):2000–5

  102. Musazzi UM, Youm I, Murowchick JB, Ezoulin MJ, Youan B-BC. Resveratrol-loaded nanocarriers: Formulation, optimization, characterization and in vitro toxicity on cochlear cells. Colloids Surf B Biointerfaces. 2014;118(0):234–42.

    Article  CAS  PubMed  Google Scholar 

  103. Wen X, Ding S, Cai H, Wang J, Wen L, Yang F, et al. Nanomedicine strategy for optimizing delivery to outer hair cells by surface-modified poly(lactic/glycolic acid) nanoparticles with hydrophilic molecules. Int J Nanomedicine. 2016;11:5959–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yoon JY, Yang KJ, Kim DE, Lee KY, Park SN, Kim DK, et al. Intratympanic delivery of oligoarginine-conjugated nanoparticles as a gene (or drug) carrier to the inner ear. Biomaterials. 2015;73:243–53.

    Article  CAS  PubMed  Google Scholar 

  105. Cai H, Wen X, Wen L, Tirelli N, Zhang X, Zhang Y, et al. Enhanced local bioavailability of single or compound drugs delivery to the inner ear through application of plga nanoparticles via round window administration. Int J Nanomedicine. 2014;9(1):5591–601.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Kim DK, Park SN, Park KH, Park CW, Yang KJ, Kim JD, et al. Development of a drug delivery system for the inner ear using poly(amino acid)-based nanoparticles. Drug Deliv. 2015;22(3):367–74.

    Article  CAS  PubMed  Google Scholar 

  107. Ge X, Jackson RL, Liu J, Harper EA, Hoffer ME, Wassel RA, et al. Distribution of PLGA nanoparticles in chinchilla cochleae. Otolaryngol Head Neck Surg. 2007;137(4):619–23.

    Article  PubMed  Google Scholar 

  108. Zhang Y, Zhang W, Löbler M, Schmitz KP, Saulnier P, Perrier T, et al. Inner ear biocompatibility of lipid nanocapsules after round window membrane application. Int J Pharm. 2011;404(1–2):211–9.

    Article  CAS  PubMed  Google Scholar 

  109. Bu M, Tang J, Wei Y, Sun Y, Wang X, Wu L, et al. Enhanced bioavailability of nerve growth factor with phytantriol lipid-based crystalline nanoparticles in cochlea. Int J Nanomedicine. 2015;10:6879–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Dash-Wagh S, Langel U, Ulfendahl M. Pepfect6 mediated siRNA delivery into organotypic cultures. Methods Mol Biol. 2016;1364:27–35.

    Article  CAS  PubMed  Google Scholar 

  111. Roy S, Johnston AH, Newman TA, Glueckert R, Dudas J, Bitsche M, et al. Cell-specific targeting in the mouse inner ear using nanoparticles conjugated with a neurotrophin-derived peptide ligand: potential tool for drug delivery. Int J Pharm. 2010;390(2):214–24.

    Article  CAS  PubMed  Google Scholar 

  112. Zou J, Hannula M, Misra S, Feng H, Labrador RH, Aula AS, et al. Micro CT visualization of silver nanoparticles in the middle and inner ear of rat and transportation pathway after transtympanic injection. J Nanobiotechnology. 2015;13(1):–5.

  113. Feng H, Pyykkö I, Zou J. Involvement of ubiquitin-editing protein A20 in modulating inflammation in rat cochlea associated with silver nanoparticle-induced CD68 upregulation and TLR4 activation. Nanoscale Res Lett. 2016; doi:10.1186/s11671-016-1430-9.

    Google Scholar 

  114. Kim JW, Lee JH, Ma JH, Chung E, Choi H, Bok J, et al. Magnetic force nanoprobe for direct observation of audio frequency tonotopy of hair cells. Nano Lett. 2016;16(6):3885–91.

    Article  CAS  PubMed  Google Scholar 

  115. Du X, Chen K, Kuriyavar S, Kopke RD, Grady BP, Bourne DH, et al. Magnetic targeted delivery of dexamethasone acetate across the round window membrane in guinea pigs. Otol Neurotol. 2013;34(1):41–7.

    Article  PubMed  PubMed Central  Google Scholar 

  116. El Kechai N, Mamelle E, Nguyen Y, Huang N, Nicolas V, Chaminade P, et al. Hyaluronic acid liposomal gel sustains delivery of a corticoid to the inner ear. J Control Release. 2016;226:248–57.

    Article  CAS  PubMed  Google Scholar 

  117. Zou J, Sood R, Ranjan S, Poe D, Ramadan UA, Kinnunen PK, et al. Manufacturing and in vivo inner ear visualization of MRI traceable liposome nanoparticles encapsulating gadolinium. J Nanobiotechnology. 2010;8:32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zou J, Sood R, Zhang Y, Kinnunen PK, Pyykko I. Pathway and morphological transformation of liposome nanocarriers after release from a novel sustained inner-ear delivery system. Nanomedicine. 2014;9(14):2143–55.

    Article  CAS  PubMed  Google Scholar 

  119. Wareing M, Mhatre AN, Pettis R, Han JJ, Haut T, Pfister MHF, et al. Cationinc liposome mediated transgene expression in guinea pig cochlea. Hear Res. 1999;128:61–9.

    Article  CAS  PubMed  Google Scholar 

  120. Tee JK, Ong CN, Bay BH, Ho HK, Leong DT. Oxidative stress by inorganic nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2016;8:414–38.

    Article  CAS  PubMed  Google Scholar 

  121. Lajud SA, Nagda DA, Qiao P, Takada N, Civantos A, Gu R, et al. A novel chitosan-hydrogel-based nanoparticle delivery system for local inner ear application. Otol Neurotol. 2015;36(2):341–7.

    Article  PubMed  PubMed Central  Google Scholar 

  122. El Kechai N, Bochot A, Huang N, Nguyen Y, Ferrary E, Agnely F. Effect of liposomes on rheological and syringeability properties of hyaluronic acid hydrogels intended for local injection of drugs. Int J Pharm. 2015;487:187–96.

    Article  CAS  PubMed  Google Scholar 

  123. Ozbakir B, Crielaard BJ, Metselaar JM, Storm G, Lammers T. Liposomal corticosteroids for the treatment of inflammatory disorders and cancer. J Control Release. 2014;190:624–36.

    Article  CAS  PubMed  Google Scholar 

  124. Gaviani P, Corsini E, Salmaggi A, Lamperti E, Botturi A, Erbetta A, et al. Liposomal cytarabine in neoplastic meningitis from primary brain tumors: a single institutional experience. Neurol Sci. 2013;34(12):2151–7.

    Article  CAS  PubMed  Google Scholar 

  125. Dan N, Danino D. Structure and kinetics of lipid-nucleic acid complexes. Adv Colloid Interf Sci. 2014;205:230–9.

    Article  CAS  Google Scholar 

  126. Wasungu L, Hoekstra D. Cationic lipids, lipoplexes and intracellular delivery of genes. J Control Release. 2006;116(2):255–64.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via G. Colombo, 71, 20133, Milan, Italy

    Umberto M. Musazzi, Silvia Franzé & Francesco Cilurzo

Authors
  1. Umberto M. Musazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Franzé
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Cilurzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Umberto M. Musazzi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Musazzi, U.M., Franzé, S. & Cilurzo, F. Innovative pharmaceutical approaches for the management of inner ear disorders. Drug Deliv. and Transl. Res. 8, 436–449 (2018). https://doi.org/10.1007/s13346-017-0384-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-017-0384-5

Keywords

Search

Navigation