%A Videhult Pierre,Pernilla %A Fransson,Anette %A Kisiel,Marta Alina %A Damberg,Peter %A Nikkhou Aski,Sahar %A Andersson,Mats %A Hällgren,Lotta %A Laurell,Göran %D 2019 %J Frontiers in Cellular Neuroscience %C %F %G English %K Auditory brainstem response (ABR),particulate chitosan,Cisplatin,Hair cell,Hearing Loss,Intratympanic administration,Magnetic resonace imaging,Sodium thiosulfate %Q %R 10.3389/fncel.2019.00268 %W %L %M %P %7 %8 2019-June-25 %9 Original Research %# %! IT particulate chitosan against ototoxicity %* %< %T Middle Ear Administration of a Particulate Chitosan Gel in an in vivo Model of Cisplatin Ototoxicity %U https://www.frontiersin.org/articles/10.3389/fncel.2019.00268 %V 13 %0 JOURNAL ARTICLE %@ 1662-5102 %X BackgroundMiddle 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.AimThis study aimed to investigate the properties of a chitosan-based particulate hydrogel formulation when used as a drug carrier for IT administration in an in vivo model of ototoxicity.Materials and MethodsTwo particulate chitosan-based IT delivery systems, Thio-25 and Thio-40, were investigated in albino guinea pigs (n = 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 in vivo. 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, in vivo 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.ResultsBoth chitosan-based IT delivery systems caused ABR threshold elevations (p < 0.05) that remained after 10 days (p < 0.05) without evidence of hair cell loss, although the elevation induced by Thio-25 was significantly lower than for Thio-40 (p < 0.05). Thio-25 significantly reduced cisplatin-induced ABR threshold elevations (p < 0.05) and outer hair cell loss (p < 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.ConclusionParticulate 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.