Effective non-viral delivery of siRNA to acute myeloid leukemia cells with lipid-substituted polyethylenimines.
Effective non-viral delivery of siRNA to acute myeloid leukemia cells with lipid-substituted polyethylenimines.
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DOI：
10.1371/journal.pone.0044197
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Uludağ H
中科院分区：
文献类型：
--
作者：
Landry B;Aliabadi HM;Samuel A;Gül-Uludağ H;Jiang X;Kutsch O;Uludağ H
使用小干扰RNA （siRNA）是一种很有前途的治疗AML的方法，因为siRNA分子可以被设计成专门针对这种疾病中导致异常细胞增殖的蛋白质。然而，由于siRNA的细胞递送存在问题，因此必须开发一种与临床相关的递送siRNA分子的方法。在这里，我们报道了两亲性载体结合阳离子聚合物（2 kDa聚乙烯亚胺，PEI2）和亲脂性部分，以促进细胞内siRNA递送到AML细胞系。设计的载体在聚合物：siRNA比为~ 0.5的条件下实现了siRNA的完全结合，并得到了尺寸为~ 100 nm的siRNA/聚合物复合物。虽然天然的PEI2对AML细胞系THP-1、KG-1和HL-60没有细胞毒性，但对PEI2的脂质修饰略微增加了细胞毒性，这与聚合物与细胞膜的相互作用增加一致。siRNA的细胞递送依赖于脂质取代的性质和脂质取代的程度，并且在使用的三种AML细胞系中有所不同。在所制备的聚合物中，亚油酸取代的聚合物表现最好，其siRNA递送量相当于性能更好的商用试剂。使用THP-1细胞和一个报告基因（GFP）和一个内源性靶标（CXCR4），在25至50 nM的siRNA浓度下实现了所选靶标的有效沉默，并且不会对随后的细胞生长产生不利影响。我们的结论是，脂质取代的PEI2可以作为siRNA到白血病细胞的有效递送，并可用于白血病的分子治疗。
Use of small interfering RNA (siRNA) is a promising approach for AML treatment as the siRNA molecule can be designed to specifically target proteins that contribute to aberrant cell proliferation in this disease. However, a clinical-relevant means of delivering siRNA molecules must be developed, as the cellular delivery of siRNA is problematic. Here, we report amphiphilic carriers combining a cationic polymer (2 kDa polyethyleneimine, PEI2) with lipophilic moieties to facilitate intracellular delivery of siRNA to AML cell lines. Complete binding of siRNA by the designed carriers was achieved at a polymer:siRNA ratio of ∼0.5 and led to siRNA/polymer complexes of ∼100 nm size. While the native PEI2 did not display cytotoxicity on AML cell lines THP-1, KG-1 and HL-60, lipid-modification on PEI2 slightly increased the cytotoxicity, which was consistent with increased interaction of polymers with cell membranes. Cellular delivery of siRNA was dependent on the nature of lipid substituent and the extent of lipid substitution, and varied among the three AML cell lines used. Linoleic acid-substituted polymers performed best among the prepared polymers and gave a siRNA delivery equivalent to better performing commercial reagents. Using THP-1 cells and a reporter (GFP) and an endogenous (CXCR4) target, effective silencing of the chosen targets was achieved with 25 to 50 nM of siRNA concentrations, and without adversely affecting subsequent cell growth. We conclude that lipid-substituted PEI2 can serve as an effective delivery of siRNA to leukemic cells and could be employed in molecular therapy of leukemia.
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