Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model
Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model
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DOI：
10.3390/cancers11030333
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发表时间：
2019-03-01
期刊：
影响因子：
5.2
通讯作者：
Koegel, Donat
中科院分区：
文献类型：
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作者：
Linder, Benedikt;Weirauch, Ulrike;Koegel, Donat
胶质母细胞瘤（GBM），WHO IV级，是成人中最具侵袭性的原发性脑肿瘤。使用标准治疗的中位生存时间仅为12-15个月，5年生存率约为5%。因此，新的和有效的治疗方式是非常重要的。信号转导子和转录激活子3（Stat 3）是驱动癌症的主要标志的关键信号传导蛋白，并且代表了用于开发靶向胶质母细胞瘤疗法的有希望的靶标。在这里，我们提出的数据显示，siRNA的治疗应用，制定在纳米级的脂质复合物（LPP）的基础上聚乙烯亚胺（PEI）和磷脂1，2-二棕榈酰-sn-甘油-3-磷酸胆碱（DPPC），代表了一个有前途的新方法，以靶向神经胶质瘤中的Stat 3。我们证明了LPP介导的siRNA递送介导了Stat 3的有效敲低，抑制了Stat 3活性并限制了体外鼠（Tu 2449）和人（U87，Mz 18）胶质瘤细胞中的细胞生长。在治疗环境中，与阴性对照处理的动物相比，颅内应用含siRNA的LPP导致携带Tu 2449神经胶质瘤的小鼠中STAT 3靶基因表达的敲低、肿瘤生长的减少和存活的显著延长。这是一项概念验证研究，介绍了基于PEI的脂聚复合物作为治疗靶向癌蛋白的有效策略，否则药物性有限。
Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12-15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. Signal transducer and activator of transcription 3 (Stat3) is a key signaling protein driving major hallmarks of cancer and represents a promising target for the development of targeted glioblastoma therapies. Here we present data showing that the therapeutic application of siRNAs, formulated in nanoscale lipopolyplexes (LPP) based on polyethylenimine (PEI) and the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), represents a promising new approach to target Stat3 in glioma. We demonstrate that the LPP-mediated delivery of siRNA mediates efficient knockdown of Stat3, suppresses Stat3 activity and limits cell growth in murine (Tu2449) and human (U87, Mz18) glioma cells in vitro. In a therapeutic setting, intracranial application of the siRNA-containing LPP leads to knockdown of STAT3 target gene expression, decreased tumor growth and significantly prolonged survival in Tu2449 glioma-bearing mice compared to negative control-treated animals. This is a proof-of-concept study introducing PEI-based lipopolyplexes as an efficient strategy for therapeutically targeting oncoproteins with otherwise limited druggability.