Cell‐based delivery system is a promising strategy to protect therapeutic agents from the immune system and provide targeted delivery. Mesenchymal stem cells (MSCs) have recently been introduced as an encouraging vehicle in cell‐based gene therapy due to their unique features including tumor‐tropic property and migratory ability. However, gene transfer into MSCs is limited due to low efficiency and cytotoxicity of carriers. In this study, we designed a novel delivery system based on polyethylenimine (PEI₂₅) to improve these features of carrier and transfect plasmid encoding TRAIL to MSCs. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is a death ligand of TNF family with selective effect on cancerous cells. Then, death induction and migration ability of TRAIL‐expressing MSCs was studied in melanoma cells. The effect of engineered‐MSCs as an antitumor vehicle was also investigated in mice bearing melanoma cells. Our findings indicated that heterocyclic amine derivative of PEI₂₅ showed significant improvement in MSCs viability determined by MTT assay and gene expression using fluorescent microscopy, flow cytometry, and Western blot analysis. We observed that engineered‐MSCs could migrate toward and induce cell death in B16F0 cells in vitro. The single administration of TRAIL‐expressing MSCs could delay tumor appearance and efficiently reduce tumor weights. Hematoxylin and eosin staining of tumor sections revealed extensive neoplastic cells necrosis. Furthermore, engineered‐MSCs could migrate and localize to tumors sites within 5 days. Our results indicated that MSCs engineered by modified‐PEI/TRAIL complexes could be considered as a promising cellular vehicle for targeted tumor suppression.

中文翻译：

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由改性聚乙烯亚胺聚合物改造的间充质干细胞用于体外和体内靶向癌症基因治疗。

基于细胞的递送系统是保护治疗剂免受免疫系统侵害并提供靶向递送的有前景的策略。间充质干细胞 (MSCs) 最近被引入作为细胞基因治疗中令人鼓舞的载体，因为它们具有独特的特性，包括向肿瘤性和迁移能力。然而，由于载体的低效率和细胞毒性，基因转移到 MSC 中受到限制。在这项研究中，我们设计了一种基于聚乙烯亚胺（PEI ₂₅) 以改善载体的这些特征并将编码 TRAIL 的质粒转染到 MSCs。肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 是 TNF 家族的死亡配体，对癌细胞具有选择性作用。然后，在黑色素瘤细胞中研究了表达 TRAIL 的 MSCs 的死亡诱导和迁移能力。还在携带黑色素瘤细胞的小鼠中研究了工程化 MSC 作为抗肿瘤载体的效果。我们的研究结果表明，PEI _{25 的}杂环胺衍生物使用荧光显微镜、流式细胞术和蛋白质印迹分析通过 MTT 测定和基因表达确定的 MSC 活力显着改善。我们观察到工程化的 MSCs 可以在体外向 B16F0 细胞迁移并诱导细胞死亡。单次给药表达 TRAIL 的 MSCs 可以延缓肿瘤的出现并有效降低肿瘤重量。肿瘤切片的苏木精和伊红染色显示广泛的肿瘤细胞坏死。此外，工程间充质干细胞可以在 5 天内迁移并定位到肿瘤部位。我们的结果表明，由修饰的 PEI/TRAIL 复合物改造的 MSCs 可被视为一种有前途的靶向肿瘤抑制细胞载体。