Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China; Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan.
Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun 130024, China.
Acta Biomater. 2018 Oct 15;80:144-153. doi: 10.1016/j.actbio.2018.09.015. Epub 2018 Sep 15.
Glioblastoma remains the most resistant malignant brain tumor owing to the lack of an efficient delivery system for therapeutic genes or drugs, especially in outgrowing tumor islands. Cell-based delivery systems such as mesenchymal stem cells (MSCs) are a potential candidate in this regard. Conventionally, MSCs have been genetically modified for cancer therapy by using viral vectors that can illicit oncogenicity and limit their use in clinical trials. In this study, we have used nonviral agents such as the polylysine-modified polyethylenimine (PEI-PLL) copolymer to generate genetically engineered MSCs with suicidal genes, namely, HSV-TK and TRAIL. Our results demonstrated that an intratumoral injection of polymer-double-transfected MSCs along with prodrug ganciclovir injections can induce a significant synergistic therapeutic response both in vitro and in vivo compared to single plasmid transfections or untransfected MSCs. The proliferation marker Ki67 and the angiogenesis marker VEGF were also significantly reduced in treatment groups, whereas the TUNEL assay demonstrated that apoptosis is significantly increased after treatment. Our findings suggest that the PEI-PLL copolymer can successfully modify MSCs with therapeutic genes and can produce a pronounced impact during glioblastoma therapy. This study proposes a potential nonviral approach to develop a cell-based therapy for the treatment of glioma. STATEMENT OF SIGNIFICANCE: In this study, we have used a polylysine-modified polyethylenimine polymer (PEI-PLL) copolymer, a non viral transfection agent, for gene delivery in mesenchymal stem cells. These PEI-PLL-transfected mesenchymal stem cells with HSV-TK and TRAIL genes have the potential to treat glioma both in vitro and in vivo. This combinational therapy through PEI-PLL-transfected mesenchymal stem cells can provide cost-effective, low immunogenic, and tumor-targeted delivery of suicideal genes (HSV-TK and TRAIL) for promising glioblastoma treatment.
胶质母细胞瘤仍然是最具耐药性的恶性脑肿瘤，因为缺乏有效的治疗基因或药物传递系统，尤其是在不断生长的肿瘤岛上。基于细胞的传递系统，如间充质干细胞（MSCs），在这方面是一个潜在的候选者。传统上，MSCs 已经通过使用能够引起致癌性的病毒载体进行了基因修饰，以用于癌症治疗，这限制了它们在临床试验中的应用。在这项研究中，我们使用了非病毒制剂，如聚赖氨酸修饰的聚亚乙基亚胺（PEI-PLL）共聚物，生成具有自杀基因（即 HSV-TK 和 TRAIL）的基因工程 MSC。我们的结果表明，与单质粒转染或未转染的 MSC 相比，肿瘤内注射聚合物双重转染的 MSC 并联合前药更昔洛韦注射，可以在体外和体内诱导显著的协同治疗反应。增殖标志物 Ki67 和血管生成标志物 VEGF 也明显减少，而 TUNEL 检测表明治疗后凋亡明显增加。我们的研究结果表明，PEI-PLL 共聚物可以成功地用治疗基因修饰 MSC，并在胶质母细胞瘤治疗中产生显著影响。这项研究提出了一种潜在的非病毒方法，用于开发用于治疗神经胶质瘤的基于细胞的疗法。
在这项研究中，我们使用了聚赖氨酸修饰的聚亚乙基亚胺聚合物（PEI-PLL）共聚物，一种非病毒转染剂，用于间充质干细胞中的基因传递。这些携带 HSV-TK 和 TRAIL 基因的 PEI-PLL 转染间充质干细胞具有在体外和体内治疗神经胶质瘤的潜力。通过 PEI-PLL 转染间充质干细胞的这种组合疗法可以为有前途的胶质母细胞瘤治疗提供具有成本效益、低免疫原性和肿瘤靶向的自杀基因（HSV-TK 和 TRAIL）的传递。
