Targeted Delivery of miRNA Antagonists to Myeloid Cells In Vitro and In Vivo.
Targeted Delivery of miRNA Antagonists to Myeloid Cells In Vitro and In Vivo.
复制标题
体外和体内将 miRNA 拮抗剂靶向递送至骨髓细胞。
DOI：
10.1007/978-1-4939-9220-1_10
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Kortylewski,Marcin
中科院分区：
文献类型：
--
作者：
Su,Yu-Lin;Swiderski,Piotr;Marcucci,Guido;Kortylewski,Marcin
癌细胞中microRNA水平的升高通常与致癌作用相关，因此提供了潜在的治疗靶点。然而，缺乏合成的miRNA抑制剂、miR抑制剂或抗miR寡核苷酸的有效递送方法阻碍了这些策略的临床转化。我们最近开发了一种方法，通过与单链硫代磷酸寡脱氧核苷酸（PSO）的连接，将合成的2′-O-甲基修饰的AlkomiR分子靶向递送至正常和恶性骨髓细胞和B细胞。通过清道夫受体介导的人单核细胞、树突细胞、B细胞以及髓性白血病和B细胞淋巴瘤细胞的内吞作用，而不是通过T细胞，PSO-β omiR被快速内化。在内化后，未配制的PSO-PSOomiR在体外和体内均有效地降低靶miRNA的水平并调节下游蛋白质靶标的表达。PSO-miR缀合物的简单设计使得能够适应这种用于靶向非恶性和恶性骨髓细胞和B细胞中的致癌miRNA的策略。
Elevated levels of microRNAs in cancer cells are often associated with oncogenic effects and thus provide potential therapeutic targets. However, the lack of efficient delivery methods for synthetic miRNA inhibitors, antagomiR, or anti-miR oligonucleotides hindered clinical translation of such strategies. We recently developed an approach for targeted delivery of synthetic, 2′-O-methyl-modified antagomiR molecules to normal and malignant myeloid cells and B cells by tethering to the single-stranded, phosphorothioate oligodeoxynucleotides (PSO). The PSO-antagomiR are rapidly internalized through scavenger receptor-mediated endocytosis by human monocytes, dendritic cells, B cells, as well as myeloid leukemia and B-cell lymphoma cells, but not by T cells. Following internalization, the unformulated PSO-antagomiR potently reduces levels of target miRNA and modulates expression of downstream protein targets, both in vitro and in vivo. The simple design of PSO-antagomiR conjugates enable adaptation of this strategy for targeting oncogenic miRNAs in nonmalignant and malignant myeloid cells and B cells.