AUTHOR=Videhult Pierre Pernilla , Fransson Anette , Kisiel Marta Alina , Damberg Peter , Nikkhou Aski Sahar , Andersson Mats , Hällgren Lotta , Laurell Göran 

TITLE=Middle Ear Administration of a Particulate Chitosan Gel in an in vivo Model of Cisplatin Ototoxicity

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=13

YEAR=2019

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2019.00268

DOI=10.3389/fncel.2019.00268

ISSN=1662-5102

ABSTRACT=<sec><title>Background</title><p>Middle ear (intratympanic, IT) administration is a promising therapeutic method as it offers the possibility of achieving high inner ear drug concentrations with low systemic levels, thus minimizing the risk of systemic side effects and drug-drug interactions. Premature elimination through the Eustachian tube may be reduced by stabilizing drug solutions with a hydrogel, but this raises the secondary issue of conductive hearing loss.</p></sec><sec><title>Aim</title><p>This study aimed to investigate the properties of a chitosan-based particulate hydrogel formulation when used as a drug carrier for IT administration in an <italic>in vivo</italic> model of ototoxicity.</p></sec><sec><title>Materials and Methods</title><p>Two particulate chitosan-based IT delivery systems, Thio-25 and Thio-40, were investigated in albino guinea pigs (<italic>n</italic> = 94). Both contained the hearing protecting drug candidate sodium thiosulfate with different concentrations of chitosan gel particles (25% vs. 40%). The safety of the two systems was explored <italic>in vivo</italic>. The most promising system was then tested in guinea pigs subjected to a single intravenous injection with the anticancer drug cisplatin (8 mg/kg b.w.), which has ototoxic side effects. Hearing status was evaluated with acoustically evoked frequency-specific auditory brainstem response (ABR) and hair cell counting. Finally, <italic>in vivo</italic> magnetic resonance imaging was used to study the distribution and elimination of the chitosan-based system from the middle ear cavity in comparison to a hyaluronan-based system.</p></sec><sec><title>Results</title><p>Both chitosan-based IT delivery systems caused ABR threshold elevations (<italic>p</italic> &lt; 0.05) that remained after 10 days (<italic>p</italic> &lt; 0.05) without evidence of hair cell loss, although the elevation induced by Thio-25 was significantly lower than for Thio-40 (<italic>p</italic> &lt; 0.05). Thio-25 significantly reduced cisplatin-induced ABR threshold elevations (<italic>p</italic> &lt; 0.05) and outer hair cell loss (<italic>p</italic> &lt; 0.05). IT injection of the chitosan- and hyaluronan-based systems filled up most of the middle ear space. There were no significant differences between the systems in terms of distribution and elimination.</p></sec><sec><title>Conclusion</title><p>Particulate chitosan is a promising drug carrier for IT administration. Future studies should assess whether the physical properties of this technique allow for a smaller injection volume that would reduce conductive hearing loss.</p></sec>