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Intracochlear Steroid Delivery to Prevent Cisplatin-Dependent Hearing Loss

Pierstorff, Erik PhD

doi: 10.1097/01.HJ.0000575368.59228.dd
Chemo-Induced Hearing Loss
Free

Dr. Pierstorff's research interests have focused on the intersection of the biotic and abiotic, spanning molecular and cell biology, gene therapy, nanomaterials, and drug delivery. For the past nine years at O-Ray Pharma, he has focused on integrating biology and biomedical engineering for the goal of drug development and sustained drug delivery for the treatment of hearing loss and other ear disorders.

As cancer treatment continues to advance, more emphasis has been placed on improving the quality of life of cancer patients. While many chemotherapeutic agents are effective, they may also come with serious side effects that can have debilitating consequences during and following a course of treatment. An area with increased interest over the past decade is the prevention of hearing loss associated with the administration of platinum-based chemotherapeutic drugs, especially cisplatin. Cisplatin, commonly used to treat a variety of solid tumors, acts primarily by facilitating DNA damage to prevent replication and induce apoptosis.1 Unfortunately, cisplatin is able to traverse the blood-labyrinthine barrier and access the inner ear. Once there, the drug appears to primarily attack outer hair cells, causing permanent hearing loss.2-6 Children are more susceptible to the ototoxic effects of cisplatin.7, 8 Hearing loss in children can impact their social and academic progress, which can have long-term effects. However, reducing the levels of cisplatin administered is not recommended, as this can reduce the tumor response and thus reduce control of the disease and lead to reoccurrence.

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At present, no drug has been approved for the prevention of cisplatin-dependent hearing loss. Multiple therapies are in human trials but the clinical success of these is yet to be determined. One issue with the use of a systemic otoprotective agent concurrently with cisplatin administration is that the otoprotective agent may interfere with cisplatin activity, making it less effective. Therefore, any otoprotective agent must either use closely timed systemic administration to elicit its protective effect but not interfere with cisplatin activity or be administered directly to the ear, localizing its activity to the area of need. Recent studies have demonstrated that cisplatin can be retained in the inner ear for months after a single administration.9 Thus, any effective otoprotectant must either prevent the cisplatin from reaching the ear or remain in the ear for months following administration.

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GETTING DRUGS INTO THE INNER EAR

The treatment of maladies of the inner ear using pharmaceutical agents is challenging. Many therapeutic agents are unable to achieve therapeutic levels in the inner ear following systemic administration. The inner ear contains the blood-labyrinthine barrier, analogous to the blood-brain barrier of the central nervous system. In many cases, the levels of systemic drug needed to achieve therapeutic levels in the inner ear cause systemic toxicity, limiting the practicality of dosing. To circumvent these problems, multiple techniques have been developed for the local delivery of drugs into the middle ear.10-19 These include intratympanic injections, micropumps and wicks, and depot systems to slowly release a drug to the middle ear/round window niche. Although all of these methods generally reduce the side effects of administered drugs and can enhance the therapeutic levels achieved in the inner ear, middle ear drug administration still has its shortcomings.20, 21 Most notable are the loss of drugs down the Eustachian tube and variability of patient anatomy (bony protrusions, false membranes, etc.), which can lead to having highly variable levels of a drug in the inner ear fluid. Thus, accurate dosing is difficult, if not impossible.

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INTRACOCHLEAR DRUG DELIVERY

The goal of our group was to develop methods and technologies to safely administer therapeutics directly into the cochlea. Although this is a more invasive route of administration, we believe that with enhanced technology and surgical techniques, intracochlear drug delivery can be a safe and more effective method for delivering pharmaceutical interventions of hearing loss. To this end, we recently published multiple reports highlighting extended release micro-pellets for the long-term delivery of steroids into the inner ear of guinea pigs. In the first study, very consistent levels of the steroid fluticasone propionate (fluticasone) were safely delivered into the perilymph for at least three months following a single intracochlear implantation of the controlled-release micro-pellets.22 In the follow-up report recently published in the International Journal of Pediatric Otorhinolaryngology,23 the activity of the released fluticasone was tested in guinea pigs, with cisplatin ototoxicity as the outcome measure.

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STUDY HIGHLIGHTS

The goal of the cisplatin study was to test if the controlled release fluticasone micro-pellets could be safely implanted into guinea pig cochleae and if the drug activity could be retained following the release from the micro-pellets. We also wanted to perform an initial assessment as to whether fluticasone could protect against cisplatin-dependent ototoxicity. It is well known that other corticosteroids (i.e., dexamethasone) have otoprotective activity in animal models, but the effectiveness of fluticasone in this scenario was previously untested.

In this study, micro-pellets were implanted into the cochleae of one ear in healthy animals, and the contralateral ear was used as a non-implanted control. After two weeks, the animals were given an intraperitoneal injection of cisplatin sufficient enough to induce hearing loss. Hearing was assessed pre-surgery, pre-cisplatin administration, and two weeks following cisplatin administration. Non-implanted ears showed significant loss in hearing via auditory brainstem response (ABR). Statistically significant hearing preservation was observed in ears implanted with the controlled-release fluticasone micro-pellets. A similar trend was observed via distortion product otoacoustic emissions (DPOAEs), though statistical significance was not achieved. We believe the lack of statistical significance for DPOAEs was due to the study's small sample size and the higher variability of DPOAE measurements. Although these studies are preliminary in nature, they suggest that intra-cochlear implantation of controlled-release fluticasone micro-pellets may evolve into a safe and viable therapeutic option to prevent cisplatin-dependent hearing loss.

The direct intracochlear administration of steroids can reduce side effects from systemic administration, prevent interference of cisplatin's anti-cancer activity in the body, and provide consistent dosing from patient to patient. This can have a profound effect on the quality of life of many cancer patients, especially children who are particularly susceptible to cisplatin-dependent hearing loss. Once the safety of the micro-pellet components are confirmed and a minimally invasive surgical technique is developed, we believe that the direct intracochlear implantation of these micro-pellets can be a safe and more effective method for the treatment of cisplatin-dependent hearing loss and other inner ear disorders.

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REFERENCES

1. Tanida S, Mizoshita T, Ozeki K, et al Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment. Int J Surg Oncol. 2012; 2012 Article ID 862879: 8 pages. doi:10.1155/2012/862879.
2. Trzaska S Cisplatin. Chem Eng News. 2005; 83(25): 52. DOI: 10.1021/cen-v083n025.p052.
3. Frisina RD, Wheeler HE, Fossa SD, et al Comprehensive audiometric analysis of hearing impairment and tinnitus after cisplatin-based chemotherapy in survivors of adult-onset cancer. J Clin Oncol. 2016 34 23 2712–2720
4. Kopelman J, Budnick AS, Sessions RB, Kramer MB, Wong GY Ototoxicity of high-dose cisplatin by bolus administration in patients with advanced cancers and normal hearing. Laryngoscope. 1988; 98(8 Pt 1): 858-864.
5. Bokemeyer C, Berger CC, Hartmann JT, et al Analysis of risk factors for cisplatin-induced otoxocity in patients with testicular cancer. Br J Canc. 1998 77 8 1355–1362
6. Knight KR, Kraemer DF, Winter C, Neuwelt EA Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol. 2007 25 10 1190–5
7. Brock PR, Knight KR, Freyer DR, et al Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale. J Clin Oncol. 2012; 30(19): 2408-2417. doi: 10.1200/JCO.2011.39.1110.
8. Knight KR, Kraemer DF, Neuwelt EA Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol. 2005 23 34 8588–96
9. Bertolini P, Lassalle M, Mercier G, et al Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss. J Pediatr Hematol Oncol. 2004 20 10 649–655
10. Zhao D, Tong B, Wang Q, Hellstrom S, Duan M A comparison of effects of systemic and intratympanic steroid therapies for sudden sensorineural hearing loss: a meta-analysis. J Otol. 2016; 11(1): 18-23. doi: 10.1016/j.joto.2016.02.002.
11. Balough BJ, Hoffer ME, Wester D, O'Leary MJ, Brooker CR, Goto M Kinetics of gentamicin uptake in the inner ear of Chinchilla langier after middle-ear administration in a sustained-release vehicle. Otolaryngol Head Neck Surg. 1998 119 5 427–31
12. Hoffer ME, Kopke RD, Weisskopf P, Gottshall K, Allen K, Wester D Microdose gentamicin administration via the round window microcatheter: results in patients with Meniere's disease. Ann N Y Acad Sci. 2001 942 46–51
13. Hoffer ME, Kopke RD, Weisskopf P, et al Use of the round window microcatheter in the treatment of Meniere's disease. Laryngoscope. 2001; 111(11 Pt 1): 2046-9.
14. Tandon V, Kang WS, Robbins TA, et al Microfabricated reciprocating micropump for intracochlear drug delivery with integrated drug/fluid storage and electronically controlled dosing. Lab Chip. 2016; 16: 829-46. doi: 10.1039/C5LC01396H.
15. Wang X, Dellamary L, Fernandez R, et al Dose-Dependent Sustained Release of Dexamethasone in Inner Ear Cochlear Fluids Using a Novel Local Delivery Approach. Audiol Neurotol. 2009; 14: 393–401. doi: 10.1159/000241896.
16. Piu F, Wang X, Fernandez R, et al OTO-104: A Sustained-Release Dexamethasone Hydrogel for the Treatment of Otic Disorders. Otol Neurotol. 2011; 32: 171-179. doi: 10.1097/MAO.0b013e3182009d29.
17. Harrop A, Wang X, Fernandez R, et al OTO-104, a Sustained Release Formulation of Dexamethasone, Offers Effective Protection Against Hearing Loss. Abstracts of the Thirty- Fourth Annual MidWinter Research Meeting of The Association for Research in Otolaryngology 2011. #638: p. 212-3.
18. Lee KY, Nakagawa T, Okano T, et al Novel Therapy for Hearing Loss: Delivery of Insulin-Like Growth Factor 1 to the Cochlea Using Gelatin Hydrogel. Otol Neurotol. 2007 28 976–981
19. Nakagawa T, Sakamoto T, Hiraumi H, et al Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: a prospective clinical trial. BMC Med. 2010; 8: 76-81. doi: 10.1186/1741-7015-8-76.
20. Sadé J Mucociliary flow in the middle ear. Ann Otol Rhinol Larngol. 1971; 80(3): 336-341. doi: 10.1177/000348947108000306.
21. Salt AN, Hartsock J, Plontke S, LeBel C, Piu F Distribution of dexamethasone and preservation of inner ear function following intratympanic delivery of a gel-based formulation. Audiol Neurotol. 2011; 16(5): 323-335. doi: 10.1159/000322504.
22. Pierstorff E, Chen S, Chaparro MP A Polymer-Based Extended Release System for Stable, Long-term Intracochlear Drug Delivery. Otol Neurotol. 2018; 39(9): 1195-1202. doi: 10.1097/MAO.0000000000001977.
23. Pierstorff E, Yang W-W, Chen J-JA, Cheung S, Kalinec F, Slattery WH Prevention of cisplatin-induced hearing loss by extended release fluticasone propionate intracochlear implants. Int J Pediatr Otorhinolaryngol. 2019; 121:157-163. doi: 10.1016/j.ijporl.2019.03.021.
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