Publication Date:
2014-11-20
Description:
MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, 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. 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. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367962/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367962/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Christopher J -- Bahal, Raman -- Babar, Imran A -- Pincus, Zachary -- Barrera, Francisco -- Liu, Connie -- Svoronos, Alexander -- Braddock, Demetrios T -- Glazer, Peter M -- Engelman, Donald M -- Saltzman, W Mark -- Slack, Frank J -- 2T32HL007974/HL/NHLBI NIH HHS/ -- F32 CA174247/CA/NCI NIH HHS/ -- F32CA174247/CA/NCI NIH HHS/ -- P30 CA016359/CA/NCI NIH HHS/ -- R00 AG042487/AG/NIA NIH HHS/ -- R01 CA131301/CA/NCI NIH HHS/ -- R01 CA148996/CA/NCI NIH HHS/ -- R01 CA149128/CA/NCI NIH HHS/ -- R01 EB000487/EB/NIBIB NIH HHS/ -- R01 ES005775/ES/NIEHS NIH HHS/ -- R01 GM073857/GM/NIGMS NIH HHS/ -- R01 HL085416/HL/NHLBI NIH HHS/ -- R01CA131301/CA/NCI NIH HHS/ -- R01CA148996/CA/NCI NIH HHS/ -- R01EB000487/EB/NIBIB NIH HHS/ -- R01ES005775/ES/NIEHS NIH HHS/ -- R01GM073857/GM/NIGMS NIH HHS/ -- R01HL085416/HL/NHLBI NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- T32 HL007974/HL/NHLBI NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Feb 5;518(7537):107-10. doi: 10.1038/nature13905. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA [3] Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA. ; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA. ; Department of Pathology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409146" target="_blank"〉PubMed〈/a〉
Keywords:
Acids
;
Animals
;
Cell Membrane/metabolism
;
Cell Membrane Permeability
;
Disease Models, Animal
;
*Drug Delivery Systems
;
Female
;
*Gene Expression Regulation, Neoplastic
;
*Gene Silencing
;
Hydrogen-Ion Concentration
;
Lymphoma/*genetics/pathology/*therapy
;
Male
;
Mice
;
MicroRNAs/*antagonists & inhibitors/genetics
;
Molecular Targeted Therapy
;
Nanoparticles/administration & dosage/chemistry
;
Oncogenes/genetics
;
Peptide Nucleic Acids/administration & dosage/chemistry/therapeutic use
;
*Tumor Microenvironment/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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