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磁性纳米颗粒作为 dsRNA 的载体用于基因治疗。

Magnetic Nanoparticles as a Carrier of dsRNA for Gene Therapy.

机构信息

Department of Molecular Neurooncology, Institute of Bioorganic Chemistry Polish Academy of Sciences, Poznan, Poland.

NanoBioMedical Centre, Adam Mickiewicz University in Poznan, Poznań, Poland.

出版信息

Methods Mol Biol. 2021;2211:69-81. doi: 10.1007/978-1-0716-0943-9_6.

Abstract

Glioma belongs to the most aggressive and lethal types of cancer. Glioblastoma multiforme (GBM), the most common type of malignant gliomas, is characterized by a poor prognosis and remains practically incurable despite aggressive treatment such as surgery, radiotherapy, and chemotherapy. Brain tumor cells overexpress a number of proteins that play a crucial role in tumorigenesis and may be exploited as therapeutic targets. One such target can be an extracellular matrix glycoprotein-tenascin-C (TN-C). Downregulation of TN-C by RNA interference (RNAi) is a very promising strategy in cancer therapy. However, the successful delivery of naked double-stranded RNA (dsRNA) complementary to TN-C sequence (ATN-RNA) requires application of delivery vehicles that can efficiently overcome rapid degradation by nucleases and poor intracellular uptake. Here, we present a protocol for application of MNP@PEI as a carrier for ATN-RNA to GBM cells. The obtained complexes consisted of polyethyleneimine (PEI)-coated magnetic nanoparticles combined with the dsRNA show high efficiency in ATN-RNA delivery, resulting not only in significant TN-C expression level downregulation, but also impairing the tumor cells migration.

摘要

神经胶质瘤属于侵袭性和致命性最强的癌症之一。多形性胶质母细胞瘤(GBM)是最常见的恶性神经胶质瘤,其预后不良,尽管采用手术、放疗和化疗等积极治疗,但实际上仍无法治愈。脑肿瘤细胞过度表达许多在肿瘤发生中起关键作用的蛋白质,这些蛋白质可能被用作治疗靶点。其中一个靶点可以是细胞外基质糖蛋白 tenascin-C(TN-C)。通过 RNA 干扰(RNAi)下调 TN-C 是癌症治疗中非常有前途的策略。然而,成功递送与 TN-C 序列互补的裸露双链 RNA(dsRNA)(ATN-RNA)需要应用能够有效克服核酸酶快速降解和细胞内摄取不良的递送载体。在这里,我们提出了一种将 MNP@PEI 作为 ATN-RNA 载体应用于 GBM 细胞的方案。所获得的复合物由聚乙烯亚胺(PEI)包覆的磁性纳米粒子与 dsRNA 组成,显示出在 ATN-RNA 递送上的高效率,不仅导致 TN-C 表达水平显著下调,而且还损害了肿瘤细胞的迁移。

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