MicroRNA silencing for cancer therapy targeted to the tumor microenvironment

SUMMARY PARAGRAPH

MicroRNAs (miRNAs) are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, miRNAs are critical cogs in numerous biological processes ^{1, 2} , and dysregulated miRNA expression is correlated with many human diseases. Certain miRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumors that depend on these miRNAs are said to display oncomiR addiction ^{3– 5} . Some of the most effective anticancer therapies target oncogenes like EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (i.e. 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 tumor microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We found that the attachment of peptide nucleic acid (PNA) antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produced a novel construct that could target the tumor microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumors (pH ~6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new paradigm in the use of antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.