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

Anisha Gupta; Elias Quijano; Yanfeng Liu; Raman Bahal; Susan E. Scanlon; Eric Song; Wei-Che Hsieh; Demetrios E. Braddock; Danith H. Ly; W. Mark Saltzman; Peter M. Glazer

doi:10.1016/j.omtn.2017.09.001

Molecular Therapy: Nucleic Acids (Dec 2017)

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

Anisha Gupta,
Elias Quijano,
Yanfeng Liu,
Raman Bahal,
Susan E. Scanlon,
Eric Song,
Wei-Che Hsieh,
Demetrios E. Braddock,
Danith H. Ly,
W. Mark Saltzman,
Peter M. Glazer

Affiliations

Anisha Gupta: Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA
Elias Quijano: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
Yanfeng Liu: Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA
Raman Bahal: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
Susan E. Scanlon: Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA
Eric Song: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
Wei-Che Hsieh: Department of Chemistry and Center for Nucleic Acids Science and Technology (CNAST), Carnegie Mellon University, Pittsburgh, PA 15213, USA
Demetrios E. Braddock: Department of Pathology, Yale University, New Haven, CT 06510, USA
Danith H. Ly: Department of Chemistry and Center for Nucleic Acids Science and Technology (CNAST), Carnegie Mellon University, Pittsburgh, PA 15213, USA
W. Mark Saltzman: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
Peter M. Glazer: Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA

DOI: https://doi.org/10.1016/j.omtn.2017.09.001
Journal volume & issue: Vol. 9, no. C
pp. 111 – 119

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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