Woo Seok Kang1, Shuting Sun, Kim Nguyen, Boris Kashemirov, Charles E McKenna, S Adam Hacking, Alicia M Quesnel, William F Sewell, Michael J McKenna, David H Jung. 1. *Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston; †Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston; ‡Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts; §Department of Chemistry, University of Southern California, Los Angeles, California; and ∥Department of Orthopaedics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.
Abstract
HYPOTHESIS: Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. BACKGROUND: Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we use a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by auditory brainstem responses and distortion product otoacoustic emissions. METHODS: 6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane, or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. RESULTS: There was a dose-dependent increase in fluorescent signal after systemic 6-FAM-ZOL treatment. Local delivery via the round window membrane or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed after either systemic or local 6-FAM-ZOL delivery. CONCLUSION: These findings establish important preclinical parameters for the treatment of cochlear otosclerosis in humans.
HYPOTHESIS: Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. BACKGROUND:Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we use a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by auditory brainstem responses and distortion product otoacoustic emissions. METHODS:6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane, or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. RESULTS: There was a dose-dependent increase in fluorescent signal after systemic 6-FAM-ZOL treatment. Local delivery via the round window membrane or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed after either systemic or local 6-FAM-ZOL delivery. CONCLUSION: These findings establish important preclinical parameters for the treatment of cochlear otosclerosis in humans.
Authors: Shuting Sun; Katarzyna M Błażewska; Boris A Kashemirov; Anke J Roelofs; Fraser P Coxon; Michael J Rogers; Frank H Ebetino; Michael J McKenna; Charles E McKenna Journal: Phosphorus Sulfur Silicon Relat Elem Date: 2011-04
Authors: Shayanne A Lajud; Zhao Han; Fang-Lu Chi; Rende Gu; Danish A Nagda; Orysia Bezpalko; Samudra Sanyal; Andres Bur; Ziying Han; Bert W O'Malley; Daqing Li Journal: J Control Release Date: 2013-01-08 Impact factor: 9.776
Authors: Jenny A F Vermeer; Ineke D C Jansen; Matangi Marthi; Fraser P Coxon; Charles E McKenna; Shuting Sun; Teun J de Vries; Vincent Everts Journal: Bone Date: 2013-08-17 Impact factor: 4.398
Authors: Anke J Roelofs; Fraser P Coxon; Frank H Ebetino; Mark W Lundy; Zachary J Henneman; George H Nancollas; Shuting Sun; Katarzyna M Blazewska; Joy Lynn F Bala; Boris A Kashemirov; Aysha B Khalid; Charles E McKenna; Michael J Rogers Journal: J Bone Miner Res Date: 2010-03 Impact factor: 6.741
Authors: Woo Seok Kang; Kim Nguyen; Charles E McKenna; William F Sewell; Michael J McKenna; David H Jung Journal: Otol Neurotol Date: 2016-07 Impact factor: 2.311
Authors: Farzad Forouzandeh; Xiaoxia Zhu; Ahmed Alfadhel; Bo Ding; Joseph P Walton; Denis Cormier; Robert D Frisina; David A Borkholder Journal: J Control Release Date: 2019-01-25 Impact factor: 9.776
Authors: Woo Seok Kang; Kim Nguyen; Charles E McKenna; William F Sewell; Michael J McKenna; David H Jung Journal: Otol Neurotol Date: 2016-03 Impact factor: 2.311
Authors: Vishal Tandon; Woo Seok Kang; Tremaan A Robbins; Abigail J Spencer; Ernest S Kim; Michael J McKenna; Sharon G Kujawa; Jason Fiering; Erin E L Pararas; Mark J Mescher; William F Sewell; Jeffrey T Borenstein Journal: Lab Chip Date: 2016-03-07 Impact factor: 6.799
Authors: Shuting Sun; Katarzyna M Błażewska; Anastasia P Kadina; Boris A Kashemirov; Xuchen Duan; James T Triffitt; James E Dunford; R Graham G Russell; Frank H Ebetino; Anke J Roelofs; Fraser P Coxon; Mark W Lundy; Charles E McKenna Journal: Bioconjug Chem Date: 2015-12-08 Impact factor: 4.774
Authors: Judith S Kempfle; Kim Nguyen; Christine Hamadani; Nicholas Koen; Albert S Edge; Boris A Kashemirov; David H Jung; Charles E McKenna Journal: Bioconjug Chem Date: 2018-02-27 Impact factor: 4.774
Authors: Taha A Jan; Aaron K Remenschneider; Christopher Halpin; Margaret Seton; Michael J McKenna; Alicia M Quesnel Journal: Laryngoscope Investig Otolaryngol Date: 2017-09-21
Authors: Judith S Kempfle; Marlon V Duro; Andrea Zhang; Carolina D Amador; Richard Kuang; Ryan Lu; Boris A Kashemirov; Albert S Edge; Charles E McKenna; David H Jung Journal: Front Cell Neurosci Date: 2021-07-15 Impact factor: 5.505