Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo
Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo
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DOI：
10.1038/nbt1366
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发表时间：
2008-01-01
影响因子：
46.9
通讯作者：
Benezra, Robert
中科院分区：
文献类型：
--
作者：
Henke, Erik;Perk, Jonathan;Benezra, Robert
转录因子是治疗多种恶性肿瘤的重要靶点，但极难抑制，因为它们位于细胞核中，主要通过蛋白质-DNA和蛋白质-蛋白质相互作用起作用。转录调节因子Id 1和Id 3是肿瘤侵袭、转移和血管生成所必需的，因此是肿瘤治疗的有吸引力的靶点。我们在这里报告的发展的抗肿瘤药物，下调Id 1有效地在体内肿瘤内皮细胞。通过将反义分子与已知特异性归巢于肿瘤新生血管的肽融合，实现肿瘤内皮中Id 1蛋白水平的有效递送和实质性降低。在两种不同的肿瘤模型中，这种药物的全身给药导致出血、缺氧和原发性肿瘤生长和转移的抑制增强，与在Id 1敲除小鼠中观察到的相似。与Hsp 90抑制剂17-（烯丙基氨基）-17-去甲氧基格尔德霉素的组合几乎完全抑制了侵袭性乳腺肿瘤的生长。
Transcription factors are important targets for the treatment of a variety of malignancies but are extremely difficult to inhibit, as they are located in the cell's nucleus and act mainly by protein-DNA and protein-protein interactions. The transcriptional regulators Id1 and Id3 are attractive targets for cancer therapy as they are required for tumor invasiveness, metastasis and angiogenesis. We report here the development of an antitumor agent that downregulates Id1 effectively in tumor endothelial cells in vivo. Efficient delivery and substantial reduction of Id1 protein levels in the tumor endothelium were effected by fusing an antisense molecule to a peptide known to home specifically to tumor neovessels. In two different tumor models, systemic delivery of this drug led to enhanced hemorrhage, hypoxia and inhibition of primary tumor growth and metastasis, similar to what is observed in Id1 knockout mice. Combination with the Hsp90 inhibitor 17-( allylamino)-17-demethoxygeldanamycin yielded virtually complete growth suppression of aggressive breast tumors.