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Efficient Nuclear Delivery and Nuclear Body Localization of Antisense Oligo-Nucleotides using Degradable Polymersomes

机译:使用可降解聚合物小体的反义寡核苷酸的有效核传递和核体定位

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摘要

Delivery of antisense oligonucleotides, AON, presents many of the same challenges as delivery of any nucleic acid: charge, stability, cell uptake, endolysosomal escape, and entry into the nucleus. Here we demonstrate efficient delivery of AON after loading into biodegradable polymer vesicles or \u27polymersomes\u27. We focus on AON delivery to muscle cells in vitro and in vivo because of the emergence of AON in therapeutic strategies directed at muscular dystrophies. To first clarify uptake kinetics without the complications of typical multi-layered myotube cultures, we use micro-patterned C2C12 cells and show efficient uptake of AON-polymersomes. The biodegradable polymersomes break down and foster AON escape with the binding of fluorescent-AON into the nuclear bodies. Intramuscular injections of the polymersome-AON into the hind limbs of mdx-dystrophic mice show more efficient nuclear uptake than AON alone and also lead to dystrophin expression in the mdx mice. In sum, these neutral, degradable carriers of AON show promise in vivo.
机译:反义寡核苷酸AON的传递面临着与任何核酸传递相同的挑战:电荷,稳定性,细胞摄取,溶酶体逃逸以及进入细胞核。在这里,我们展示了加载到可生物降解的聚合物囊泡或聚合物囊泡中后,AON的有效递送。由于AON在针对肌肉营养不良的治疗策略中的出现,因此我们专注于在体外和体内将AON递送至肌肉细胞。为了首先阐明摄取动力学,而没有典型的多层肌管培养的复杂性,我们使用了微模式的C2C12细胞,并显示了AON-多聚体的有效摄取。可生物降解的聚合物囊泡分解并促进AON逃逸,同时荧光AON结合到核体内。向mdx营养不良的小鼠的后肢肌肉注射多聚体-AON比单独的AON更有效地吸收核,并且在mdx小鼠中导致肌营养不良蛋白的表达。总之,这些中性,可降解的AON载体在体内显示出了希望。

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