Videhult Pierre Pernilla, Fransson Anette, Kisiel Marta Alina, Damberg Peter, Nikkhou Aski Sahar, Andersson Mats, Hällgren Lotta, Laurell Göran
Division of Audiology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Front Cell Neurosci. 2019 Jun 25;13:268. doi: 10.3389/fncel.2019.00268. eCollection 2019.
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.
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 model of ototoxicity.
Two particulate chitosan-based IT delivery systems, Thio-25 and Thio-40, were investigated in albino guinea pigs ( = 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 . 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, 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.
Both chitosan-based IT delivery systems caused ABR threshold elevations ( < 0.05) that remained after 10 days ( < 0.05) without evidence of hair cell loss, although the elevation induced by Thio-25 was significantly lower than for Thio-40 ( < 0.05). Thio-25 significantly reduced cisplatin-induced ABR threshold elevations ( < 0.05) and outer hair cell loss ( < 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.
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.
中耳（鼓室内，IT）给药是一种很有前景的治疗方法，因为它有可能在全身药物水平较低的情况下实现内耳高药物浓度，从而将全身副作用和药物相互作用的风险降至最低。通过用凝胶稳定药物溶液，可以减少通过咽鼓管的过早消除，但这会引发传导性听力损失的次要问题。
本研究旨在研究一种基于壳聚糖的颗粒状水凝胶制剂在耳毒性模型中用作IT给药的药物载体时的特性。
在白化豚鼠（n = 94）中研究了两种基于壳聚糖的颗粒状IT递送系统，Thio-25和Thio-40。两者都含有听力保护候选药物硫代硫酸钠以及不同浓度的壳聚糖凝胶颗粒（25%对40%）。探索了这两种系统的安全性。然后在接受单次静脉注射抗癌药物顺铂（8 mg/kg体重）（具有耳毒性副作用）的豚鼠中测试了最有前景的系统。用听觉诱发频率特异性听性脑干反应（ABR）和毛细胞计数评估听力状况。最后，与基于透明质酸的系统相比，使用磁共振成像研究基于壳聚糖的系统在中耳腔中的分布和消除情况。
两种基于壳聚糖的IT递送系统均导致ABR阈值升高（P < 0.05），10天后仍保持升高（P < 0.05），且无毛细胞损失的证据，尽管Thio-25引起的升高明显低于Thio-40（P < 0.05）。Thio-25显著降低了顺铂诱导的ABR阈值升高（P < 0.05）和外毛细胞损失（P < 0.05）。IT注射基于壳聚糖和透明质酸的系统充满了大部分中耳空间。在分布和消除方面，两种系统之间没有显著差异。
颗粒状壳聚糖是一种很有前景的IT给药药物载体。未来的研究应评估该技术的物理特性是否允许使用更小的注射体积，从而减少传导性听力损失。
