Conjugation with receptor-targeted histidine-rich peptides enhances the pharmacological effectiveness of antisense oligonucleotides.
Conjugation with receptor-targeted histidine-rich peptides enhances the pharmacological effectiveness of antisense oligonucleotides.
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DOI：
10.1021/bc400500h
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发表时间：
2014-01-15
影响因子：
4.7
通讯作者：
Juliano, Rudy
中科院分区：
文献类型：
--
作者：
Nakagawa, Osamu;Ming, Xin;Carver, Kyle;Juliano, Rudy
无效递送至细胞内作用位点是使用反义寡核苷酸和siRNA寡核苷酸作为治疗剂的关键限制之一。在这里，我们描述了分子规模的反义寡核苷酸缀合物，选择性地结合到细胞表面受体，被内化，然后部分地从非生产性内体位置逃逸，到达其在细胞核中的作用位点。将包括用于受体靶向的蛙皮素序列和用于内体破坏的组氨酸残基的肽共价连接至剪接转换反义寡核苷酸。测试缀合物在表达铃蟾肽受体的前列腺癌细胞中校正剪接和上调荧光素酶报告基因表达的能力。我们发现，包括靶向序列和几个组氨酸残基的三价缀合物基本上比仅含有蛙皮素或组氨酸部分的缀合物更有效。这证明了产生具有靶向和内体逃逸能力的分子规模寡核苷酸缀合物的潜力。
Ineffective delivery to intracellular sites of action is one of the key limitations to the use of antisense and siRNA oligonucleotides as therapeutic agents. Here, we describe molecular scale antisense oligonucleotide conjugates that bind selectively to a cell surface receptor, are internalized, and then partially escape from nonproductive endosomal locations to reach their sites of action in the nucleus. Peptides that include bombesin sequences for receptor targeting and a run of histidine residues for endosomal disruption were covalently linked to a splice switching antisense oligonucleotide. The conjugates were tested for their ability to correct splicing and up-regulate expression of a luciferase reporter in prostate cancer cells that express the bombesin receptor. We found that trivalent conjugates that included both the targeting sequence and several histidine residues were substantially more effective than conjugates containing only the bombesin or histidine moieties. This demonstrates the potential of creating molecular scale oligonucleotide conjugates with both targeting and endosome escape capabilities.
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