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EGF receptor targeted lipo-oligocation polyplexes for antitumoral siRNA and miRNA delivery

机译：EGF受体靶向的脂质寡聚复合物可用于抗肿瘤siRNA和miRNA递送

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摘要

Antitumoral siRNA and miRNA delivery was demonstrated by epidermal growth factor receptor (EGFR) targeted oligoaminoamide polyplexes. For this purpose, the T-shaped lipo-oligomer 454 was used to complex RNA into a core polyplex, which was subsequently functionalized with the targeting peptide ligand GE11 via a polyethylene glycol (PEG) linker. To this end, free cysteines on the surface of 454 polyplex were coupled with a maleimide-PEG-GE11 reagent (Mal-GE11). Resulting particles with sizes of 120-150 nm showed receptor-mediated uptake into EGFR-positive T24 bladder cancer cells, MDA-MB 231 breast cancer cells and Huh7 liver cancer cells. Furthermore, these formulations led to ligand-dependent gene silencing. RNA interference (RNAi) triggered antitumoral effects were observed for two different therapeutic RNAs, a miRNA-200c mimic or EG5 siRNA. Using polyplexes modified with a ratio of 0.8 molar equivalents of Mal-GE11, treatment of T24 or MDA-MB 231 cancer cells with miR-200c led to the expected decreased proliferation and migration, changes in cell cycle and enhanced sensitivity towards doxorubicin. Delivery of EG5 siRNA into Huh7 cells resulted in antitumoral activity with G2/M arrest, triggered by loss of mitotic spindle separation and formation of mono-astral spindles. These findings demonstrate the potential of GE11 ligand-containing RNAi polyplexes for cancer treatment.
机译：通过表皮生长因子受体（EGFR）靶向的寡氨基酰胺复合物证明了抗肿瘤siRNA和miRNA的传递。为此，使用T形脂寡聚体454将RNA复合成核心复合体，随后将其通过聚乙二醇（PEG）接头与靶向肽配体GE11进行功能化。为此，将454复合物表面上的游离半胱氨酸与马来酰亚胺-PEG-GE11试剂（Mal-GE11）偶联。所得的大小为120-150 nm的颗粒显示出受体介导的对EGFR阳性T24膀胱癌细胞，MDA-MB 231乳腺癌细胞和Huh7肝癌细胞的摄取。此外，这些制剂导致配体依赖性基因沉默。对于两种不同的治疗性RNA，即miRNA-200c模拟物或EG5 siRNA，观察到了RNA干扰（RNAi）引发的抗肿瘤作用。使用以0.8摩尔当量的Mal-GE11比例修饰的多链体，用miR-200c处理T24或MDA-MB 231癌细胞可导致预期的增殖和迁移减少，细胞周期变化以及对阿霉素的敏感性增强。 EG5 siRNA传递到Huh7细胞中导致抗肿瘤活性和G2 / M阻滞，这是由有丝分裂纺锤体分离的丧失和单星形纺锤体的形成触发的。这些发现证明了含有GE11配体的RNAi多聚体在癌症治疗中的潜力。

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