Semicircular canal drug delivery safely targets the inner ear perilymphatic space
Jinkyung Kim, Jesus Maldonado, Dorothy W. Pan, Patricia M. Quiñones, Samantha Zenteno, John S. Oghalai, Anthony J. Ricci
Jinkyung Kim, Jesus Maldonado, Dorothy W. Pan, Patricia M. Quiñones, Samantha Zenteno, John S. Oghalai, Anthony J. Ricci
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Research Article Otology Therapeutics

Semicircular canal drug delivery safely targets the inner ear perilymphatic space

Abstract

Effective, reproducible, and safe delivery of therapeutics into the inner ear is required for the prevention and treatment of hearing loss. A commonly used delivery method is via the posterior semicircular canal (PSCC); however, its specific targeting within the cochlea remains unclear, impacting precision and reproducibility. To assess safety and target specificity, we conducted in vivo recordings of the pharmacological manipulations delivered through the PSCC. Measurements of auditory brainstem response (ABR), vibrometry, and vestibular behavioral and sensory-evoked potential (VsEP) revealed preserved hearing and vestibular functions after artificial perilymph injections. Injection of curare, a mechanoelectrical transducer (MET) channel blocker that affects hearing when in the endolymph, had no effect on ABR or VsEP thresholds. Conversely, injection of CNQX, an AMPA receptor blocker, or lidocaine, a Na+ channel blocker, which affects hearing when in the perilymph, significantly increased both thresholds, indicating that PSCC injections selectively target the perilymphatic space. In vivo tracking of gold nanoparticles confirmed their exclusive distribution in the perilymph during PSCC injection, supporting the pharmacological finding. Together, PSCC injection is a safe method for inner ear delivery, specifically targeting the perilymphatic space. Our findings will allow for precise delivery of therapeutics within the inner ear for therapeutic and research purposes.

Authors

Jinkyung Kim, Jesus Maldonado, Dorothy W. Pan, Patricia M. Quiñones, Samantha Zenteno, John S. Oghalai, Anthony J. Ricci

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Figure 5

Auditory brainstem response (ABR) after pharmacological manipulations through the PSCC.

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Auditory brainstem response (ABR) after pharmacological manipulations th...
(A) Illustration of cochlea with the PSCC injection, where sky blue represents perilymph and yellow represents endolymph. (B) The zoomed-in images of the box in panel A showing possible entry pathways of the PSCC injection, to the perilymph (top), endolymph (middle), or both perilymph and endolymph (bottom). (C) The cross-sectional image of the cochlea shows perilymph and endolymph-filled chambers. The magnified image of the box shows the locations of mechanoelectrical transducer (MET) channel in the inner hair cell (IHC), AMPA receptor at the level of the IHC basolateral membrane, and the Na+ channel in the nerve fibers that synapse with the IHC. (D) The table shows the predicted drug effect on ABR results depending on the compartment (perilymph or endolymph) of entry. (E) Representative ABR responses at 16 kHz in preinjection and 1 hour after curare injection. Green lines indicate thresholds of the ABR responses. (F) ABR thresholds in preinjection and 1 hour after curare injection (n = 5). P > 0.05 by paired, 2-tailed Student’s t test. (G) ABR thresholds of each individual mouse at 16 kHz in preinjection and 1 hour after curare injection (yellow box in panel F). (H) Representative ABR responses at 16 kHz in preinjection and 1 hour after CNQX injection. Red lines indicate thresholds of the ABR responses. (I) ABR thresholds in preinjection and 1 hour after CNQX injection (n = 5). *P < 0.05, **P < 0.01, ***P < 0.001 by paired, 2-tailed Student’s t test. (J) ABR thresholds of each individual mouse at 16 kHz in preinjection and 1 hour after CNQX injection (yellow box in panel I). (K) Representative ABR responses at 16 kHz in preinjection and 1 hour after lidocaine injection. Orange lines indicate thresholds of the ABR responses. (L) ABR thresholds in preinjection and 1 hour after lidocaine injection (n = 5). *P < 0.05, **P < 0.01, ***P < 0.001 by paired, 2-tailed Student’s t test. (M) ABR thresholds of each individual mouse at 16 kHz in preinjection and 1 hour after lidocaine injection (yellow box in panel L).