Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy
Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy
复制标题
具有靶向特性的胚胎干细胞衍生的外泌体作为胶质母细胞瘤治疗的化疗药物递送载体
DOI：
10.1002/advs.201801899
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发表时间：
2019
期刊：
影响因子：
15.1
通讯作者：
Zhifeng Deng
中科院分区：
文献类型：
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作者：
Qingwei Zhu;Xiaozheng Ling;Yunlong Yang;Juntao Zhang;Qing Li;Xin Niu;Guowen Hu;Bi Chen;Haiyan Li;Yang Wang;Zhifeng Deng
简介：胶质瘤治疗受到血脑屏障（BBB）的严重阻碍，这导致治疗剂的靶向活性非常有限。外泌体是一种纳米级的细胞外囊泡，具有穿透血脑屏障的能力，是治疗胶质瘤的理想药物载体。然而，一些报道已经证明，注射的外泌体主要分布在肝脏和脾脏中而不是大脑中。本研究发现胚胎干细胞来源的exosomes（ES-Exos）具有广谱的抗肿瘤活性，包括胶质瘤，因此我们进一步将ES-Exos作为紫杉醇（PTX）的载体，并在其上修饰肿瘤靶向配体cRGD。通过插入后方法将cRGD与cRGD-DSPE-PEG 2000（cRGD-Exos）结合到ES-Exos的表面上，并通过共孵育将PTX负载到cRGD-Exos中以得到cRGD-Exos-PTX。脑内注射胶质瘤细胞建立小鼠原位胶质瘤模型。使用体内成像来测试cRGD-Exos-PTX的生物分布。此外，还建立了小鼠皮下肿瘤以评估ES-Exos和cRGD-Exos-PTX的抗肿瘤能力。结果如下：我们的研究结果表明，ES-Exos可以抑制广谱肿瘤细胞的增殖，包括U87，U251，A549，HCC，HepG 2，B16，MDA-MB-231和DU 145。流式细胞仪分析显示ES-Exos诱导肿瘤细胞凋亡。此外，在cRGD修饰后，cRGD-Exos与ES-Exos相比显示出增强的肿瘤细胞摄取。活体成像分析显示cRGD-Exos在小鼠脑胶质瘤部位分布较多.用cRGD-Exos-PTX治疗的原位胶质瘤小鼠比用Exos-PTX治疗的小鼠活得更长。最后，cRGD-Exos-PTX在皮下肿瘤模型中显示出良好的抗肿瘤能力。总结/结论：在这项研究中，我们证明了ES-Exos是稳定的，并且它们的肿瘤部位分布通过cRGD修饰而增强。cRGD-Exos-PTX是治疗胶质瘤的有效治疗剂。
Introduction: Glioma treatment is severely hindered by blood brain barrier (BBB) which leads to very lim- ited on-target activity of therapeutic agents. Exosomes are nanosized extracellular vesicles with efficient BBB penetration ability and presents a promising drug car- rier for glioma treatment. However, several reports have demonstrated that injected exosomes mainly dis- tribute in liver and spleen rather than brain. In this study, we find embryonic stem cell derived exosomes (ES-Exos) show broad spectrum anti-tumour ability including glioma, and thus we further use ES-Exos as paclitaxel (PTX) carrier and modify them with tumour targeting ligand cRGD.Methods: CCK-8 analysis and flow cell analysis were used to test the anti-tumour ability of ES-Exos. cRGD was incorporated onto the surface of ES-Exos by post- insertion methods with cRGD-DSPE-PEG2000 (cRGD- Exos), and PTX was loaded into cRGD-Exos by co- incubation to get cRGD-Exos-PTX. In situ glioma model of mice was built by injecting glioma cells in brain. In vivo imaging was used to test the biodistribu- tion of cRGD-Exos-PTX. Further, subcutaneous tumour of mice was also built to evaluate the anti- tumour ability of ES-Exos and cRGD-Exos-PTX. Results: Our results showed that ES-Exos could inhibit tumour cell proliferation of broad spectrum, including U87, U251, A549, HCC, HepG2, B16, MDA-MB-231 and DU145. Flow cell analysis showed that ES-Exos induced tumour cell apoptosis. Furthermore, after cRGD modification, cRGD-Exos showed enhanced tumour cell uptake compared with ES-Exos. And in vivo imaging analysis demonstrated that more cRGD- Exos distributed in glioma site in mice brain. And mice with in situ glioma treated with cRGD-Exos-PTX lived more longer than the group treated with Exos-PTX. Finally, cRGD-Exos-PTX showed the beat anti-tumour ability in subcutaneous tumour model. Summary/Conclusion: In this study, we demonstrate that ES-Exos is antineoplastic, and their tumour site distribution is enhanced by cRGD modification. cRGD-Exos-PTX is an efficient therapeutic agent for glioma treatment.