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Magnetic Delivery of Therapy to the Cochlea

Depireux, Didier A. PhD; Ramaswamy, Bharath PhD; Shimoji, Mika PhD; Shukoor, Mohammed PhD; Benhal, Prateek PhD; Shapiro, Benjamin PhD

doi: 10.1097/01.HJ.0000521759.00742.6b
Magnetic Injection of Therapy

Dr. Depireux is a senior research scientist at the Institute for Systems Research at the University of Maryland and a cofounder of Otomagnetics. Dr. Ramaswamy is a scientist with the Pfizer Global Supply group. Dr. Shimoji is a senior life scientist at Otomagnetics, where Dr. Shukoor is a research chemist and material scientist. Dr. Benhal is a post-doc at the Fischell Department of Bioengineering at the University of Maryland, where Dr. Shapiro is a professor while also serving as the president of Otomagnetics.

The inner ear, like the brain, is behind a blood-labyrinth barrier. This means the blood vessels that supply blood to the inner ear's cochlea and vestibular system have vessel walls that are largely impermeable to drugs and therapy (Hear Res. 1992;61[1-2]:12 http://bit.ly/2rrihsZ; Int Tinnitus J. 2001;7[2]:72 http://bit.ly/2rrPgxx). For this reason, only one out of every 107 drug molecules administered systemically reaches the cochlea (Laryngoscope. 1999;109[7 Pt 2]:1 http://bit.ly/2rrv6Ug). The inner ear is also protected by the anatomy of the skull, and cannot be reached by a syringe injection (Expert Opin Drug Deliv. 2011;8[9]:1161 http://bit.ly/2rrQw3J). In lieu of direct delivery to the inner ear, trans-tympanic injections fill the middle ear with a drug, after which only approximately one in every 40,000 drug molecules reach the cochlea (Otol Neurotol. 2007;28[8]:1124 http://bit.ly/2rrCZcc). No matter how new or novel the drug or therapy, if it does not reach the inner ear in sufficient and effective quantities, it will not improve hearing loss, suppress tinnitus, alleviate vertigo, or reverse any of these conditions.

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MAGNETIC DELIVERY

Magnetic fields have the potential to effectively and non-invasively deliver therapy to the cochlea and the vestibular system. As first shown in rodents by Kopke, et al., in 2006, a magnetic field can transport magnetic nanoparticles from the middle ear through the window membranes and into the cochlea where they can then release their therapeutic payload (Audiol Neurootol. 2006;11[2]:123 http://bit.ly/2rrvSAE). But since single magnets can only pull (attract) nanoparticles, Kopke and colleagues placed the magnet on the side of the head opposite the treated ear, and the magnetic field pulled through the head's entire width. Scaling up this approach to human head sizes means using unacceptably large magnets and magnetic fields.

Instead, our team at the University of Maryland and at Otomagnetics developed a magnetic injection that is anticipated to enable effective drug delivery in human patients. In previous studies on small and large animals and on human cadavers, we tested a compact magnet device that can push or “magnetically inject” therapy into the cochlea. This device uses an array of small permanent magnets to create a magnetic field cancellation behind the particles, and the resulting field can push the nanoparticles away from the device and into the cochlea (Annu Rev Biomed Eng. 2014;16:455 http://bit.ly/2rrD4wB; ENT & Aud News, 2014 http://bit.ly/2rrOOzk; IEEE Trans Magn. 2013;49:440 http://bit.ly/2rrABSK). It is also small and compact, and can operate over the 3-5 cm magnet-to-cochlea distance needed for adult human patients (Fig. 1; IEEE Trans Magn. 2013 http://bit.ly/2rrABSK). To maximize safety, we developed bio-compatible iron-oxide nanoparticles composed solely of FDA-approved materials that can be safely injected into the human body. The pores in these particles can be filled with small or large molecule drugs, proteins, or genes, thereby allowing the delivery of existing and emerging therapies directly into the inner ear.

Experiments have shown that magnetic injection forces can substantially improve delivery of therapy to the cochlea. In pilot human cadaver studies, magnetic forces delivered 1,000 times more drug to the cochlea than trans-tympanic administration of the same drug. In animal studies, increased drug delivery to the cochlea has provided a strong therapeutic effect, even when delivering existing, off-the-shelf drugs (e.g., anti-inflammatory corticosteroids). Magnetic delivery of new and emerging therapies is anticipated to hold even greater promise.

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HEARING PROTECTION & RESTORATION

Magnetic delivery of the anti-inflammatory corticosteroid prednisolone can protect hearing from cisplatin chemotherapy regimens (Fig. 2). Platin-based chemotherapy regimens cause hearing loss in adult patients and even more so in children, and hearing loss is in fact listed on the label as a dose-limiting toxicity for cisplatin (J Clin Oncol. 2006;24[6]:918 http://bit.ly/2rrv8vd). We used the mouse cisplatin hearing loss model developed at the NIH to evaluate the efficacy of magnetic injection in preventing hearing loss (J Clin Invest. 2013;123[11]:4945 http://bit.ly/2rrWZLM). In animals that received only saline to their middle ears after their cisplatin regimens, their ears had complete hearing loss at high frequencies as measured by auditory brainstem recordings; in the corresponding region of the cochlea, 72 percent of the outer hair cells were missing.

In ears that received trans-tympanic prednisolone (no particles, no magnet), the high-frequency hearing was still completely lost; and in the corresponding region of the cochlea, 33 percent of the outer hair cells were missing. In contrast, ears that received magnetic delivery of prednisolone on average retained half of their high-frequency hearing, and only nine percent of the outer hair cells were missing in the high-frequency region of the cochlea. As seen in Figure 2, the magnetic forces delivered the drug-loaded nanoparticles (stained red) all the way to the vicinity of the outer hair cells, and we believe this targeted delivery is what preserved the hair cells and protected hearing. Optimizing dose and delivering more powerful and novel therapies is expected to further improve outcomes.

Our animal studies have also shown that magnetic delivery can restore hearing after it has been damaged by noise trauma. Noise trauma centered on 16 kHz (one-third octave) was administered for one hour at 118 dB SPL to rats. One day after the trauma, the traumatized ears were treated with the following:

* trans-tympanic saline in the middle ear (group A);

* magnetic delivery of prednisolone-laden nanoparticles to the cochlea (group B, the test group); and

* magnetic delivery of bare (no steroid) particles to the cochlea (group C).

To assess hearing, behavioral audiograms were conducted two days before and six days after the noise trauma. In these behavioral studies, the startle response of animals was measured. When the rat can hear a “pre-pulse” warning sound, its subsequent startle reflex to a loud and unexpected sound is reduced. Rats with normal hearing display a “pre-pulse/no pre-pulse” ratio of close to one half. Rats with poor hearing startle equally with or without a pre-pulse warning; hence, their “pre-pulse/no pre-pulse” ratio is close to unity. Figure 3 shows the experimental results. Animals in group B, whose traumatized ears received magnetic delivery of prednisolone, exhibited good hearing at 16-20 kHz, compared with those in groups A (saline) and C (bare particles, no steroid).

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PLETHORA OF USES

Animal studies show that magnetic injection of therapy to the cochlea may help suppress tinnitus (Sarwar, et al., 9th Int Conf on the Scientific and Clinical Applications of Magnetic Carriers, 2012; 6th Int Conf on Tinnitus. 2012:19 http://bit.ly/2rs0odC). Studies on large animals and human cadavers also demonstrated that this method allows for the delivery of a greater amount of drug than trans-tympanic delivery, the current standard-of-care for conditions like sudden sensorineural hearing loss and Ménière's disease. Safety studies in small animals have shown no harm to hearing and no other adverse events such as chronic inflammation, scarring, or hemorrhage in ear tissues. Despite the high concentration of therapy delivered to the cochlea, the systemic exposure to the drug and nanoparticles is very low since the administration is topical.

Mass spectrometry studies have shown that the amount of drug and nanoparticles in the blood and major organs (heart, liver, spleen, kidney, brain, adrenal glands) is below detection limits after our magnetic delivery. This opens the possibility of reconsidering the drugs and therapies that would be efficacious against inner ear disorders but display unacceptable systemic toxicities. With magnetic injection, concentrated doses of such therapies can be delivered only to the inner ear, expanding the promising uses of this delivery system in treating various hearing conditions.

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