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Mol Ther Nucleic Acids. 2017 Dec 15;9:111-119. doi: 10.1016/j.omtn.2017.09.001. Epub 2017 Sep 12.

Anti-tumor Activity of miniPEG-γ-Modified PNAs to Inhibit MicroRNA-210 for Cancer Therapy.

Author information

1
Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA.
2
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
3
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
4
Department of Chemistry and Center for Nucleic Acids Science and Technology (CNAST), Carnegie Mellon University, Pittsburgh, PA 15213, USA.
5
Department of Pathology, Yale University, New Haven, CT 06510, USA.
6
Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA; Department of Genetics, Yale University, New Haven, CT 06510, USA. Electronic address: peter.glazer@yale.edu.

Abstract

MicroRNAs (miRs) are frequently overexpressed in human cancers. In particular, miR-210 is induced in hypoxic cells and acts to orchestrate the adaptation of tumor cells to hypoxia. Silencing oncogenic miRs such as miR-210 may therefore offer a promising approach to anticancer therapy. We have developed a miR-210 inhibition strategy based on a new class of conformationally preorganized antisense γ peptide nucleic acids (γPNAs) that possess vastly superior RNA-binding affinity, improved solubility, and favorable biocompatibility. For cellular delivery, we encapsulated the γPNAs in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Our results show that γPNAs targeting miR-210 cause significant delay in growth of a human tumor xenograft in mice compared to conventional PNAs. Further, histopathological analyses show considerable necrosis, fibrosis, and reduced cell proliferation in γPNA-treated tumors compared to controls. Overall, our work provides a chemical framework for a novel anti-miR therapeutic approach using γPNAs that should facilitate rational design of agents to potently inhibit oncogenic microRNAs.

KEYWORDS:

PLGA nanoparticles; PNA; anti-miR; cancer; hypoxia; miR-210; miRNA; oncogenic miRs; γPNA

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