Kocas Meryem, Yamashita Fumiyoshi, Comoglu Tansel, Zhang Qiyue
Faculty of Pharmacy, Department of Pharmaceutical Technology, Selcuk University, Selçuklu, Konya, 42130, Turkey.
Graduate School of Health Sciences, Ankara University, Dışkapı, Ankara, 06610, Turkey.
AAPS PharmSciTech. 2025 May 2;26(5):123. doi: 10.1208/s12249-025-03113-8.
Ivermectin (IVM), an antiparasitic drug approved by the Food and Drug Administration (FDA), is widely used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies. Additionally, IVM has shown potential as a potent inhibitor of certain RNA viruses, such as SARS-CoV-2. However, IVM is highly hydrophobic, essentially insoluble in water, which limits its bioavailability and therapeutic effectiveness. The use of liposomes as drug carriers offers several advantages, including enhanced solubility for lipophilic drugs, passive targeting of immune system cells, sustained release, and improved tissue penetration. To address the limitations of IVM, including its poor solubility and bioavailability, liposomal formulations were developed using a combination of soyphosphatidylcholine (SPC), dioleylphosphatidylcholine (DOPC), cholesterol (Ch), and diethylphosphate (DCP) in two distinct molar ratios (1.85:1:0.15 and 7:2:1) via the ethanol injection method. The physicochemical properties of the placebo and IVM-loaded liposomes were extensively characterized in our earlier study, including the particle size, polydispersity index, and zeta potential. The present work adds a deeper level of investigation into how to effect cellular uptake and cytotoxicity in vitro of both free IVM and IVM-loaded liposomes in Vero E6 cells. The half-maximal cytotoxic concentrations (CC) for free IVM and IVM-loaded liposomes were 10 μM and > 110 μM, respectively and the cellular uptake of IVM-loaded liposomes ranged from 13 to 60%, whereas free IVM showed a significantly lower uptake of only 2%. These results demonstrate that liposomal encapsulation effectively enhances IVM's cellular uptake while reducing its cytotoxicity, thus offering a promising strategy for improving the effectiveness of IVM.
伊维菌素（IVM）是一种经美国食品药品监督管理局（FDA）批准的抗寄生虫药物，广泛用于治疗多种被忽视的热带病，包括盘尾丝虫病、蠕虫病和疥疮。此外，伊维菌素已显示出作为某些RNA病毒（如严重急性呼吸综合征冠状病毒2，SARS-CoV-2）的有效抑制剂的潜力。然而，伊维菌素具有高度疏水性，基本不溶于水，这限制了其生物利用度和治疗效果。使用脂质体作为药物载体具有多个优点，包括提高亲脂性药物的溶解度、被动靶向免疫系统细胞、持续释放以及改善组织渗透。为了解决伊维菌素的局限性，包括其溶解度差和生物利用度低的问题，通过乙醇注入法，以两种不同的摩尔比（1.85:1:0.15和7:2:1）将大豆磷脂酰胆碱（SPC）、二油酰磷脂酰胆碱（DOPC）、胆固醇（Ch）和磷酸二乙酯（DCP）组合，开发了脂质体制剂。在我们早期的研究中，对空白脂质体和载药脂质体的物理化学性质进行了广泛表征，包括粒径、多分散指数和zeta电位。目前的工作对游离伊维菌素和载药脂质体在体外对非洲绿猴肾细胞（Vero E6细胞）的细胞摄取和细胞毒性影响进行了更深入的研究。游离伊维菌素和载药脂质体的半数最大细胞毒性浓度（CC）分别为10 μM和>110 μM，载药脂质体的细胞摄取率在13%至60%之间，而游离伊维菌素的摄取率显著较低，仅为2%。这些结果表明，脂质体包封有效地增强了伊维菌素的细胞摄取，同时降低了其细胞毒性，从而为提高伊维菌素的疗效提供了一种有前景的策略。
