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Nanomedicine for Inner Ear Diseases: A Review of Recent In Vivo Studies.

1. Introduction

Hearing loss is a common feature of many inner ear conditions, including presbycusis, sudden sensorineural hearing loss (SSNHL), genetic diseases, noise-induced hearing loss, ototoxic hearing loss, and autoimmune inner ear disease. The prevalence of hearing loss due to these inner ear diseases is increasing because of an increase in life expectancy, exposure to noise, and the use of medicines such as anticancer drugs.

These inner ear diseases remain intractable, and treatment results are poor. One of several reasons for their intractability is that the drug does not readily reach the inner ear. When a drug is administered systemically, it must cross the blood labyrinth barrier (BLB) to reach the inner ear [1]. However, only a small amount of the drug crosses the BLB and reaches the inner ear. Therefore, high doses of medication must be administered to achieve the appropriate drug concentration in the inner ear and have a therapeutic effect. However, systemic administration of high drug concentrations, particularly steroids, has numerous side effects.

Intratympanic drug injection has been used to address these problems and has become the standard treatment for Meniere's disease and sudden deafness [2, 3]. In some ways, the inner ear is well suited to local delivery of drugs. Local delivery bypasses the BLB, allowing drugs to reach their intended target at a lower dose. Thus, higher drug concentrations can be achieved while systemic effects are minimized. However, the drug concentration in the inner ear obtained through intratympanic drug injection remains low.

Several methods have been proposed to improve the efficiency of intratympanic drug injection, such as use of the Silverstein Microwick (Micromedics, St. Paul, MN), microcatheter implantation, hydrogels, and nanoparticles [4]. In this report, we focus on in vivo studies in the otologic field using nanoparticles within the past 5 years. In theory, nanoparticle-based drug delivery can enhance the efficiency of delivery to the inner ear and release drugs in a sustained manner [5]. Nanoparticles also provide physical protection in vivo for delicate drug structures [6].

2. Challenges with Inner Ear Drug Delivery

The first challenge is ensuring the safety of the drug carrier in the middle or inner ear [7]. Nanoparticles have been used extensively in cancer therapy where cell viability is not an important issue; however, safety is an absolute requirement for nanoparticle applications for the treatment of deafness. To increase permeability into cells or to perform gene transfer, a positively charged moiety such as a cell-penetrating peptide can be attached to the nanoparticle [8, 9]. However, because positively charged nanoparticles can be ototoxic through limited biodegradability of the particle, the production of intracellular reactive oxygen species, and damage of cell membranes, their application to hearing loss is limited [10]. In addition, it must be determined whether the constituent materials of the nanoparticles will accumulate in the inner ear and be cleared or remain in the inner ear and whether these materials are toxic to hair cells.

When a drug is administered to the middle ear through intratympanic drug injection, it must pass the round window membrane (RWM) or the annular ligament of the oval window (OW) to reach the inner ear. It remains unclear whether these two windows are crossed through diffusion or endocytosis [11]. However, the drug must remain in the middle ear cavity for a sufficient amount of time and remain in contact with these two windows to be delivered to the inner ear. Unfortunately, drugs that enter the middle ear cavity do not remain and are quickly discharged to the Eustachian tube through mucociliary flow of the middle ear [12]. In response to this, gels have been studied in many animal studies. Other studies have used thermosensitive gels, which exist in a liquid state at room temperature and a gel state at body temperature [13].

Another challenge with intratympanic drug delivery is the low permeability of the RWM and annular ligament of the OW. Although the dominant entry route for the inner ear remains unknown, the RWM seems to be the dominant route. Salt et al. [14] reported distribution of an ionic marker, trimethylphenylammonium (TMPA), in the cochlea after intracochlear injection or application to the round window niche based on direct monitoring using a TMPA selective electrode or sequential collection of perilymph. Atotalof65% of TMPA entered through the RWM while 35% entered the vestibule in the vicinity of the stapes. However, in clinical situations, RWM may be blocked by fat or fiber tissue; fat or fiber tissue can interfere with drug delivery through the RWM [15]. Factors such as size, configuration, concentration, liposolubility, electrical charge, and membrane thickness influence permeability [16]. Smaller agents are transported more readily through the RWM. Zou et al. [17] explored size-dependent nanoparticle transport. Three sizes of liposome nanoparticles (95,130, and 240 nm) were manufactured, and their distribution was measured after transtympanic injection in rats. The 95 nm particles were transported most easily whereas the 240 nm particles were transported least easily. With regard to charge, in rodents cationic ferritin readily passes through the normal RWM, whereas anionic ferritin does not [16,18].

3. Studies Investigating the Uptake or Toxicity of Nanoparticles in the Inner Ear

Wen et al. [19] explored several surface-modified PLGA nanoparticles for inner ear drug delivery, of which poloxamer 407-PLGA nanoparticles showed the greatest cellular uptake and strongest fluorescence based on cochlear imaging. It is possible to analyze quantitatively the amount of nanoparticle entering the cochlea using a near-infrared fluorescence imaging system after cochlea harvest (Table 1). However, a more physiological and accurate method would be to analyze quantitatively the cochlea in a live state. This may be accomplished by isolating the perilymph and determining the concentration of the drug using HPLC. However, it is difficult to quantify drug absorbed in cells of the inner ear (not the perilymph) using this method.

In addition, inner ear drug delivery studies using superparamagnetic nanoparticles and chitosan hydrogel-based nanoparticles have recently been published, and both showed good safety and drug delivery efficiency [20, 21] (Table 1).

4. Studies Attempting to Deliver Actual Drugs to the Inner Ear Using Nanoparticles

In recent years, rather than simply investigating the permeation of nanoparticles into the inner ear, a growing number of reports have loaded a drug onto the nanoparticle and transferred it to the inner ear to observe functional changes (Table 2).

Drug delivery using polyethylene glycol-coated polylactic acid (PEG-PLA) nanoparticles has been attempted twice by the same group [22, 23]. This group used cisplatin to deafen guinea pigs after pretreatment systemically or intratympanically with dexamethasone-loaded nanoparticles. In both studies, administration of dexamethasone-loaded nanoparticles protected hearing in the 4 kHz and 8 kHz frequencies. In another study in which 6a-methylprednisolone was loaded onto nanoparticles using alpha-tocopherol derivatives, cisplatin-induced hearing loss was protected at 10, 14, and 16 kHz [24].

Other reports (excluding the aforementioned studies) have not evaluated changes in hearing after the administration of nanoparticles but instead have analyzed quantitatively the concentration of drug delivered to the inner ear based on high-performance liquid chromatography (HPLC) or fluorescence spectrophotometry [25-28]. One interesting study proposed intratympanic drug injection as a potential brain drug delivery route by analyzing the drug concentration in brain tissue and cerebrospinal fluid (CSF) after intratympanic drug administration [26]. Multiple agent-loaded nanoparticles following intratympanic injection in guinea pigs significantly improved drug distribution within the inner ear, CSF, and brain tissues and protected the brain from cerebral ischemia reperfusion injury.

5. Studies Attempting to Deliver Growth Factors to the Inner Ear Using Nanoparticles

The delivery of macromolecules including growth factors to the inner ear may be more clinically useful than simple drug delivery. This is because in individuals with chronic hearing loss, hair cells cannot be regenerated through drug delivery, although they may be facilitated by the delivery of growth factors or genes. Brain-derived neurotrophic factor (BDNF) has been investigated in many animal studies and can preserve the population of spiral ganglion neurons after hair cell loss [37, 38]. It is also considered a candidate growth factor for reversing hearing loss [39].

Recently, several studies have explored the ability of BDNF and NGF to deliver growth factors to the inner ear; however, many of these studies used intracochlear delivery [29-32] (Table 3). Because intracochlear delivery requires surgery and can lead to the loss of remnant hearing by opening the cochlea, it can only be attempted in completely deaf patients, such as for cochlear implant surgery. Intratympanic delivery is more useful because of easy clinical access. However, delivering a large macromolecule such as a growth factor remains challenging.

6. Studies Attempting to Deliver Genes to the Inner Ear Using Nanoparticles

A safe and useful nonviral gene delivery system has very high clinical value and can be used to deliver genes to patients with congenital or chronic hearing loss. For example, genes such as Atohl can potentially regenerate hair cells in patients with chronic hearing loss, such as presbycusis.

Two recent studies have attempted gene transfer using GFP fluorescence as a positive transfer marker [8, 33] (Table 4). However, it remains difficult to analyze quantitatively the amount of gene delivered to the inner ear using this method because of autofluorescence of the inner ear and the vulnerability of fluorescence intensity to the laser of a confocal microscope. In one of these studies, pRK5Atoh1-EGFP plasmids were transferred and gene transfer was analyzed quantitatively based on RT-PCR and Western blot, which appeared to be a reliable approach [33]. Although this report did not assess structural or functional changes after atohl delivery, these results demonstrate the possibility of the possibility of nonviral gene delivery through nanoparticles.

Several challenges with gene delivery using nanoparticles must be addressed before it can be applied clinically, such as decreasing the particle size while stably integrating the gene into the particle; administering a gene and nanoparticle complex to the body; protecting the gene from degrading enzymes such as endonuclease; and ensuring that the gene enters the cytoplasm, escapes the endosome, and enters the nucleus.

7. Inner Ear Drug Delivery Studies with Imaging Modalities

Direct observation of drugs or nanoparticles in the inner ear w with micro-CT or MRI can be used for quantitative analysis of the amount or distribution of a drug delivered to the cochlea. Zou et al. [34] recently injected silver nanoparticles (Ag NPs) intratympanically and observed the distribution of Ag NPs in the middle and inner ear using micro-CT, showing a gradient concentration from the middle ear to the inner ear (Table 5).

It is possible to detect the distribution of nanoparticles within the inner ear using MRI if the nanoparticles contain paramagnetic agents such as gadolinium chelate [40]. In a recent study, gadolinium chelate was encapsulated in a liposome nanocarrier and the distribution of nanoparticles in the inner ear after intratympanic injection was observed using MRI [35]. In addition to nanoparticles containing gadolinium, superparamagnetic iron oxide nanoparticles (SPION) or ceric ammonium nitrate oxidant-stabilized gamma-maghemite nanoparticles were identified in the inner ear using MRI after intratympanic or intracochlear administration [36, 41].

8. Conclusion

The use of nanoparticles is a promising therapy for inner ear disease. The ideal nanocarrier should be able to permeate the RWM or the annular ligament on the OW, be capable of specific targeting, provide controlled release of the loaded materials, and be safe in the inner ear. Many studies have attempted to deliver drugs, genes, and growth factors to the inner ear in vivo, and promising results have been reported. The safe and effective delivery of drugs or genes will be an important advancement for the treatment of many inner ear diseases, including age-related hearing loss, which is currently a refractory disease.


The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see lbQYk7.

Conflicts of Interest

The author declares that there are no conflicts of interest regarding the publication of this paper.


This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education (NRF2017R1D1A1B03027894) and the Catholic Medical Center Research Foundation in program year 2017.


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Dong-Kee Kim

Department of Otolaryngology-Head and Neck Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea

Correspondence should be addressed to Dong-Kee Kim;

Received 18 July 2017; Accepted 30 August 2017; Published 10 October 2017

Academic Editor: Kenneth H. Lee
Table 1: Studies investigating the uptake or toxicity of nanoparticles
in the inner ear.

Nanoparticle               Size of           Animal

Poloxamer 407-PLGA        181.5 nm         Guinea pigs
NP [19]

Superparamagnetic       100, 200, and      Guinea pigs
NP [20]                 500 nm (three

Chitosan-hydrogel-         160 nm         C57BL/6J mice
based NP [21]

Nanoparticle           Administration    Loaded drug or
                            route             gene

Poloxamer 407-PLGA      Intratympanic          DiR
NP [19]

Superparamagnetic       Intracochlear         None
NP [20]

Chitosan-hydrogel-      Intratympanic    Fluorescent dye
based NP [21]

Nanoparticle           Evaluation time      Evaluation of

Poloxamer 407-PLGA         At 24 h          Near-infrared
NP [19]                                  fluorescence imaging
                                           system, confocal

Superparamagnetic         At 7 days      Toxicity evaluation
NP [20]                                         by ABR

Chitosan-hydrogel-         At 24 h           Fluorescent
based NP [21]                                 microscopy

PLGA: poly(lactic/co/glycolic acid); NP: nanoparticle; DiR: 1,1/
-dioctadecyl-3,3,3/,3-tetramethylindotricarbocyanine iodide; ABR:
auditory brainstem response.

Table 2: Studies attempting to deliver actual drugs to the inner ear
using nanoparticles.

Nanoparticle           Size of             Animal

PEG-PLA NP          Not described        Guinea pig,
[22]                                    deafened with

PEG-PLA NP        130 [+ or -] 4.78      Guinea pig,
[23]                      nm            deafened with

Multimicellar       120.8-159.9 nm      Wistar rats,
NP [24]                                 deafened with

PLGA NP [25]        135 nm with a        Guinea pigs
                     PDI of 0.17

PLGA NP [26]         154 nm with         Guinea pigs
                      PDI 0.007

PLGA-             482.8 [+ or -] 158     Guinea pigs
magnetite-NP              nm

Cubic liquid        138.6-210.9 nm       Guinea pigs
crystalline NP

Nanoparticle      Administration       Loaded drug or
                       route                gene

PEG-PLA NP        Intraperitoneal      Dexamethasone

PEG-PLA NP         Intratympanic       Dexamethasone

Multimicellar      Intratympanic         6[alpha]-
NP [24]                              methylprednisolone

PLGA NP [25]       Intratympanic    Salvianolic acid B,
                                    tanshinone IIA, and
                                        total panax

PLGA NP [26]       Intratympanic    Salvianolic acid B,
                                    tanshinone IIA, and
                                        total panax

PLGA-              Intratympanic       Dexamethasone
magnetite-NP                              acetate

Cubic liquid       Intratympanic         Earthworm
crystalline NP                      fibrinolytic enzyme

Nanoparticle      Evaluation time       Evaluation of

PEG-PLA NP           At 3 days             ABR and
[22]                                     morphology

PEG-PLA NP           At 3 days             ABR and
[23]                                     morphology

Multimicellar        At 3 days              ASSR
NP [24]

PLGA NP [25]        At several             HPLC of
                   predetermined          perilymph
                    time points
                    within 96 h

PLGA NP [26]        At several         HPLC of blood,
                   predetermined       perilymph, CSF,
                    time points       and brain tissue
                    within 36 h

PLGA-                At 30 min             HPLC of
magnetite-NP                           perilymph, RWM,
[27]                                and inner ear tissue

Cubic liquid        At several          Fluorescence
crystalline NP     predetermined       microscope and
[28]                time points       spectrophotometer
                    within 24 h

NP: nanoparticle; ABR: auditory brainstem response; PEG-PLA:
polyethylene glycol-coated polylactic acid; ASSR: auditory steady-
state responses; RWM: round window membrane.

Table 3: Studies attempting to deliver growth factors to the inner ear
using nanoparticles.

Nanoparticle            Size of                 Animal

Silica            500 [micro]m (porous     Deafened guinea
supraparticle          structure)                pigs
[29, 30]

Phytantriol          215.6-227.2 nm          Guinea pigs,
lipid-based                                 deafened with
crystalline                                   cisplatin
NP [31]

Nanoporous PGA          1.8-3.2              Guinea pig,
NP [32]                                     deafened with

Nanoparticle         Administration         Loaded drug or
                         route                   gene

Silica               Intracochlear               BDNF
[29, 30]

Phytantriol          Intratympanic               NGF
NP [31]

Nanoporous PGA       Intracochlear               BDNF
NP [32]

Nanoparticle        Evaluation time         Evaluation of

Silica                 At 4 weeks          Survival ofSGNs
[29, 30]

Phytantriol            At several           ELISA assay of
lipid-based          predetermined          cochlear fluid
crystalline        time points within
NP [31]                   24 h

Nanoporous PGA         At 20 days             Morphology
NP [32]

Table 4: Studies attempting to deliver genes to the inner ear using

Nanoparticle            Size of                 Animal

PHEA NP [16]            103.1 nm             C57/BL6 mice

Dendrimer-         132 [+ or -] 20 nm       Sprague Dawley
based NP [33]                                    rats

Nanoparticle         Administration          Loaded drug
                         route                 or gene

PHEA NP [16]         Intratympanic           GFP plasmid
                                               DNA and

Dendrimer-           Intratympanic            Atoh1-EGFP
based NP [33]                                  plasmid

Nanoparticle        Evaluation time         Evaluation of

PHEA NP [16]            At 48 h                Confocal

Dendrimer-             At 7 days               Confocal
based NP [33]                                microscope,
                                             RT-PCR, and
                                             Western blot

NP: nanoparticle; PHEA: poly(2-hydroxyethyl L-aspartamide).

Table 5: Inner ear drug delivery studies with imaging modalities.

Nanoparticle                 Size of                 Animal

Silver NP [34]           21 [+ or -] 8 nm        Sprague Dawley

Liposome                115 [+ or -] 10 nm       Sprague Dawley
nanocarrier                                           rats

Ceric ammonium               50-60 nm            Sprague Dawley
nitrate oxidant-                                      rats
stabilized gamma-
maghemite NP [36]

Nanoparticle              Administration         Loaded drug or
                              route                   gene

Silver NP [34]            Intratympanic               None

Liposome                  Intratympanic             Gd-DOTA

Ceric ammonium            Intratympanic               None
nitrate oxidant-
stabilized gamma-
maghemite NP [36]

Nanoparticle             Evaluation time         Evaluation of

Silver NP [34]          At 4, 7, and 24 h           Micro-CT
                          and at 7 days

Liposome                    At several           MRI, ABR, and
nanocarrier               predetermined           inflammatory
[35]                    time points within     biological markers
                              7 days

Ceric ammonium              At several                MRI
nitrate oxidant-          predetermined
stabilized gamma-       time points within
maghemite NP [36]            14 days

NP: nanoparticle; Gd-DOTA: gadolinium-tetra-azacyclo-dodecane-tetra-
acetic acid; ABR: auditory brainstem response.
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Date:Jan 1, 2017
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