title: MicroRNA silencing for cancer therapy targeted to the tumour microenvironment.
abstract: 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.
authors.affiliation: 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.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cheng
authors.affiliation: Department of Therapeutic Radiology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Raman
authors.initials: R
authors.lastname: Bahal
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Imran A
authors.initials: IA
authors.lastname: Babar
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Pincus
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Barrera
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Svoronos
authors.affiliation: Department of Pathology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Demetrios T
authors.initials: DT
authors.lastname: Braddock
authors.affiliation: Department of Therapeutic Radiology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Engelman
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
mesh_terms: D000143:Acids; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006863:Hydrogen-Ion Concentration; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009857:Oncogenes / Q000235:genetics; D020135:Peptide Nucleic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D000143:Acids; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D020135:Peptide Nucleic Acids