Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
Microvasc Res. 2022 Sep;143:104385. doi: 10.1016/j.mvr.2022.104385. Epub 2022 May 21.
Exosomes are endogenous nanoparticles with a lipid bilayer membrane whose natural function as carriers of biological materials has attracted much attention. The ability of exosomes to cross biological barriers, especially the blood-brain barrier, has highlighted them as tools of drug delivery to brain tumors. In a previous study, we isolated and characterized exosomes derived from human endometrial mesenchymal stem cells (hEnMSCs exosomes). In the present study, we used hEnMSCs exosomes as carriers for atorvastatin and investigated its pro-apoptotic and anti-angiogenic effects on U87 glioblastoma spheroids 3D co-cultured with Human Umbilical Vein Endothelial cells (HUVECs). In the study of HUVEC proliferation by using MTT assay, cell treatments with concentrations of 5 and 10 μM of free atorvastatin and atorvastatin-loaded hEnMSCs exosomes (AtoEXOs) showed significant differences in inhibition of proliferation compared to other concentrations. Also, 5 and 10 μM of AtoEXOs inhibited HUVEC migration in both scratch closure and transwell migration assays significantly more than that of free atorvastatin. In addition, in vitro HUVEC capillary tube network formation was inhibited by 5 and 10 μM treatment of AtoEXOs significantly more that of free atorvastatin. Moreover, a significant decrease in VEGF secretion and a significant increase in Bax/Bcl2 expression ratio were observed in U87 spheroids 3D co-cultured with HUVECs, especially for 10 μM AtoEXOs compared to other treated cell groups. Our results showed that hEnMSCs exosomes loaded with atorvastatin not only mimicked the anti-tumor effects of free atorvastatin but also potentiated its anti-tumor effects on glioblastoma cells. The enhanced pro-apoptotic and anti-angiogenic capabilities of atorvastatin loaded in hEnMSCs exosomes offer promising new perspectives for the treatment of glioblastoma.
外泌体是具有双层脂膜的内源性纳米颗粒，其作为生物材料载体的自然功能引起了广泛关注。外泌体能够穿越生物屏障，特别是血脑屏障，这使其成为递送至脑肿瘤的药物载体。在之前的研究中，我们分离并鉴定了来源于人子宫内膜间充质干细胞（hEnMSCs 外泌体）的外泌体。在本研究中，我们使用 hEnMSCs 外泌体作为载体包裹阿托伐他汀，并研究其对与脐静脉内皮细胞（HUVECs）共培养的 U87 神经胶质瘤球体的促凋亡和抗血管生成作用。在使用 MTT 法检测 HUVEC 增殖的研究中，与其他浓度相比，浓度为 5 和 10 μM 的游离阿托伐他汀和载阿托伐他汀的 hEnMSCs 外泌体（AtoEXOs）对增殖的抑制作用具有显著差异。此外，与游离阿托伐他汀相比，5 和 10 μM 的 AtoEXOs 对划痕封闭和 Transwell 迁移实验中的 HUVEC 迁移均具有显著的抑制作用。此外，与游离阿托伐他汀相比，5 和 10 μM 的 AtoEXOs 处理可显著抑制体外 HUVEC 毛细血管网络形成。此外，在与 HUVEC 共培养的 U87 球体 3D 中，与其他处理的细胞组相比，观察到 VEGF 分泌显著减少和 Bax/Bcl2 表达比值显著增加，尤其是 10 μM 的 AtoEXOs。我们的结果表明，载阿托伐他汀的 hEnMSCs 外泌体不仅模拟了游离阿托伐他汀的抗肿瘤作用，而且增强了其对神经胶质瘤细胞的抗肿瘤作用。载于 hEnMSCs 外泌体的阿托伐他汀增强的促凋亡和抗血管生成能力为治疗神经胶质瘤提供了新的前景。
