Targeted delivery of doxorubicin to HER2 positive tumor models
Targeted delivery of doxorubicin to HER2 positive tumor models
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DOI：
10.2147/ijn.s210731
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发表时间：
2019-01-01
影响因子：
8
通讯作者：
Khodashenas, Shabanali
中科院分区：
文献类型：
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作者：
Gomari, Hosna;Moghadam, Mehdi Forouzandeh;Khodashenas, Shabanali
背景资料：外泌体是具有独特特征的天然纳米囊泡，例如长循环半衰期、靶向组织的内在能力、生物相容性和最小或无固有全身毒性。间充质干细胞产生大量的外泌体，具有再生特性，在人血浆中更稳定。方法：从转导的骨髓间充质干细胞中分离靶向的exosomes。通过电穿孔将多柔比星包封到外泌体中。流式细胞术用于评估外泌体与靶细胞的附着。采用MTT法测定靶向阿霉素外泌体对TUBO细胞的体外细胞毒性作用。通过在体成像系统测量阿霉素的自体荧光来分析阿霉素向肿瘤组织的选择性递送。此外，在TUBO乳腺癌模型中注射游离多柔比星以及靶向和非靶向负载多柔比星的外泌体后监测肿瘤生长抑制和体重。结果：流式细胞术结果显示靶向外泌体与HER2阳性（46.05%）和HER2阴性（13.9%）细胞的结合存在显著差异。MTT法结果显示，靶向阿霉素外泌体的细胞毒性在72小时时高于游离阿霉素。靶向的载有多柔比星的外泌体在鼠乳腺癌模型的靶组织中的选择性分布表明通过靶向的外泌体而不是非靶向的外泌体特异性递送多柔比星。游离阿霉素和非靶向阿霉素加载的外泌体表现出不显著的影响，而靶向阿霉素加载的外泌体降低了肿瘤的生长率。结论：在这里，我们报告了有效的目标阿霉素加载的外泌体在体外，证实了小鼠乳腺癌模型肿瘤生长率的显着降低。
Background: Exosomes are natural nanovesicles with unique characteristics, such as long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent systemic toxicity. Mesenchymal stem cells produce large amounts of exosomes with regenerative properties and more stability in human plasma. TUBO breast cancer cell lines overexpress rat HER2/neu protein.Methods: Targeted exosomes were isolated from transduced bone marrow mesenchymal stem cells. Doxorubicin was encapsulated into exosomes by electroporation. Flow cytometry was used to assess the attachment of exosomes to the target cells. The in vitro cytotoxicity effect of targeted doxorubicin-loaded exosomes on TUBO cells was determined using MTT assay. Selective delivery of doxorubicin to tumor tissues was analyzed by measuring the auto-fluorescence of doxorubicin by in vivo imaging system. Moreover, tumor growth inhibition and body weight were monitored following injection of free doxorubicin, and targeted and untargeted doxorubicin-loaded exosomes in a TUBO breast cancer model. Finally, mouse tissues were examined for the presence of intrinsic fluorescence of doxorubicin.Results: Flow cytometry results revealed significant differences in binding of targeted exosomes to HER2-positive (46.05%) and HER2-negative (13.9%) cells. The results of MTT assay showed that cytotoxicity of targeted doxorubicin-loaded exosomes was higher than free doxorubicin at 72 hours. Selective distribution of targeted doxorubicin-loaded exosomes in the target tissues of the murine breast cancer model suggested specific delivery of doxorubicin by targeted exosomes, rather than untargeted exosomes. Free doxorubicin and untargeted doxorubicin-loaded exosomes showed insignificant effects, whereas targeted doxorubicin-loaded exosomes reduced the tumor growth rate.Conclusion: Herein, we report efficient delivery of targeted doxorubicin-loaded exosomes in vitro, corroborated with a significant reduction of murine breast cancer model tumor growth rate.