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.
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;24:918 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;123:4945 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).
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.Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.