MicroRNA silencing for cancer therapy targeted to the tumour microenvironment

• Published in: Nature (London) Vol. 518; no. 7537; pp. 107 - 110
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.02.2015; Nature Publishing Group
• Subjects: 42; 42/89; 631/154/152; 631/61/391/2310; 631/67/1059/602; 631/67/395; 64/60; Acids; Animals; Cancer; Cancer therapies; Care and treatment; Cell Membrane - metabolism; Cell Membrane Permeability; Disease Models, Animal; Drug Delivery Systems; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetic aspects; Health aspects; Humanities and Social Sciences; Hydrogen-Ion Concentration; letter; Lymphatic system; Lymphocytes; Lymphoma; Lymphoma - genetics; Lymphoma - pathology; Lymphoma - therapy; Male; Metastasis; Mice; MicroRNA; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; Molecular Targeted Therapy; multidisciplinary; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nucleic acids; Oncogenes - genetics; Peptide Nucleic Acids - administration & dosage; Peptide Nucleic Acids - chemistry; Peptide Nucleic Acids - therapeutic use; Peptides; Science; Tumor Microenvironment - genetics; Tumors; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13905

A novel anti-microRNA delivery platform that targets the acidic tumour microenvironment, in which a chosen anti-miRNA is coupled to a peptide that can transport the anti-miRNA across cell membranes specifically in an acidic environment. Targeted delivery of oncomiRNAs The targeted silencing of certain aberrantly expressed microRNAs (miRNAs) — known as oncomiRs — may prove useful for cancer therapy if the silencing agents can be efficiently delivered to the tumours. Frank Slack and colleagues now exploit the generally acidic tumour environment by devising nanoparticle-based delivery vehicles in which a chosen anti-miR is coupled to a peptide that can transport the anti-miR across cell membranes specifically in an acidic environment. In a lymphoma mouse model, this formulation can specifically target anti-miR-155 to those tumours whose growth depends on miR-155 expression, reducing tumour growth and metastases without apparent toxicity to the mice. This approach should be widely applicable for targeting a variety of tumours with an anti-miR of choice. 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 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 , 4 , 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.