期刊
NATURE
卷 518, 期 7537, 页码 107-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13905
关键词
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资金
- Ruth L. Kirschstein Postdoctoral Fellowship from the National Cancer Institute/National Institutes of Health (NCI/NIH) [F32CA174247]
- NCI/NIH [R01CA131301, R01CA148996]
- National Heart, Lung, and Blood Institute (NHLBI)/NIH [R01HL085416]
- National Institute of General Medical Sciences (NIGMS)/NIH [R01GM073857]
- National Institute of Environmental Health Sciences (NIEHS)/NIH [R01ES005775]
- National Institute of Biomedical Imaging and Bioengineering (NIBIB)/NIH [R01EB000487]
- NHLBI/NIH [2T32HL007974]
- Yale Comprehensive Cancer Center
MicroRNAs are short non-codingRNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs innumerous biological processes(1,2), and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction(3-5). Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy(6,7). However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells(8). Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.
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