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Artemisinin Loaded mPEG-PCL Nanoparticle Based Photosensitive Gelatin Methacrylate Hydrogels for the Treatment of Gentamicin Induced Hearing Loss.
International Journal of Nanomedicine ( IF 8 ) Pub Date : 2020-06-25 , DOI: 10.2147/ijn.s245188
Xiaohua Li 1 , Yanchun Wang 2 , Feilong Xu 1 , Feng Zhang 1 , Ying Xu 3 , Lei Tang 3 , Thomas J Webster 4
Affiliation  

Objective: Artemisinin (ART) is a natural anti-malarial sesquiterpene lactone which has the ability to treat and activate the CLRN1 pathway to play a pivotal role in hearing loss and hair cell function. To investigate the therapeutic effect of ART in hearing loss induced by gentamicin (GM), an ART-loaded poly(ethylene glycol)-b-poly(ϵ-caprolactone) mPEG-PCL nanoparticle-based photosensitive hydrogel was developed and tested in this study.
Materials and Methods: Artemisinin-loaded mPEG-PCL nanoparticles (mPEG-PCL-ART-NPs) were prepared by a double emulsion method and the formulation was optimized by an orthogonal experimental design. The particle size, zeta potential, morphology and in vitro dissolution of the mPEG-PCL-ART-NPs were well characterized. Biocompatibility of the mPEG-PCL-ART-NPs were tested on HeLa cells with an MTT assay. The photo-crosslinkable biodegradable gelatin methacrylate (GelMA) hydrogel was prepared and its physicochemical properties (such as substitution, photocrosslinking efficiency, cell viability morphology, mechanical and swelling properties) were evaluated. Finally, mPEG-PCL-ART-FITC-NPs, loaded mPEG-PCL-ART-NPs, and loaded mPEG-PCL-ART-NPs-GelMA hydrogels were fabricated and a GM toxicity-induced guinea pig ear damage model was established to determine the effectiveness of the materials on returning auditory function and cochlea pathomorphology.
Results: The zeta potential of the mPEG-PCL-ART-NPs was about − 38.64 ± 0.21 mV and the average size was 167.51 ± 1.87 nm with an encapsulation efficacy of 81.7 ± 1.46%. In vitro release studies showed that the mPEG-PCL-ART-NPs possessed a sustained-release effect and the MTT experiments showed good biocompatibility properties of the drug-loaded nanoparticles. The results indicated that the 5% GelMA with MA-4% hydrogel had a better crosslinking density and 3D structure for drug loading and drug delivery than controls. Skin penetration results showed that the mPEG-PCL-ART-NPs increased adhesive capacity and avoided fast diffusion in the skin. Most importantly, auditory brainstem response results indicated that the mPEG-PCL-ART-NPs-GelMA hydrogel alleviated hearing loss induced by GM.
Conclusion: These results suggested that the presently fabricated mPEG-PCL-ART-NPs-GelMA hydrogels are promising formulations for the treatment of hearing loss induced by GM and lay the foundation for further clinical research of inner ear induction therapy.

Keywords: artemisinin, mPEG-PCL nanoparticles, GelMA hydrogel, hearing loss, gentamicin


中文翻译:

青蒿素负载 mPEG-PCL 纳米颗粒基于光敏明胶甲基丙烯酸酯水凝胶用于治疗庆大霉素引起的听力损失。

目的:青蒿素(Artemisinin,ART)是一种天然抗疟倍半萜内酯,具有治疗和激活CLRN1通路的能力,在听力损失和毛细胞功能中发挥关键作用。为了研究 ART 在庆大霉素 (GM) 引起的听力损失中的治疗效果,本研究开发并测试了一种载有 ART 的聚(乙二醇)-b-聚(ε-己内酯)mPEG-PCL 纳米颗粒光敏水凝胶。 .
材料和方法:采用双乳法制备载青蒿素的mPEG-PCL纳米粒(mPEG-PCL-ART-NPs),并通过正交实验设计优化配方。mPEG-PCL-ART-NPs 的粒径、zeta 电位、形态和体外溶出度都得到了很好的表征。mPEG-PCL-ART-NPs 的生物相容性在 HeLa 细胞上用 MTT 法进行了测试。制备了可光交联的生物可降解明胶甲基丙烯酸酯(GelMA)水凝胶,并对其物理化学性质(如取代度、光交联效率、细胞活力形态、力学和溶胀性能)进行了评价。最后,mPEG-PCL-ART-FITC-NPs,加载 mPEG-PCL-ART-NPs,
结果: mPEG-PCL-ART-NPs 的 zeta 电位约为 - 38.64 ± 0.21 mV,平均尺寸为 167.51 ± 1.87 nm,封装效率为 81.7 ± 1.46%。体外释放研究表明,mPEG-PCL-ART-NPs具有缓释作用,MTT实验表明载药纳米粒子具有良好的生物相容性。结果表明,与对照相比,5% GelMA 与 MA-4% 水凝胶具有更好的交联密度和 3D 结构的载药和药物递送。皮肤渗透结果表明,mPEG-PCL-ART-NPs 增加了粘附能力并避免了在皮肤中的快速扩散。最重要的是,听觉脑干反应结果表明 mPEG-PCL-ART-NPs-GelMA 水凝胶减轻了 GM 引起的听力损失。
结论:这些结果表明,目前制备的 mPEG-PCL-ART-NPs-GelMA 水凝胶是治疗 GM 引起的听力损失的有前景的制剂,为进一步开展内耳诱导治疗的临床研究奠定了基础。

关键词:青蒿素,mPEG-PCL纳米粒,GelMA水凝胶,听力损失,庆大霉素
更新日期:2020-06-30
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