Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 9, Issue -, Pages 111-119Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2017.09.001
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Funding
- NIH [R35CA197574, R01ES005775, R01CA168733]
- NIH/NIGMS [T32GM007205]
- National Science Foundation [CHE-1609159]
- DSF Charitable Foundation
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1609159] Funding Source: National Science Foundation
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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 gamma peptide nucleic acids (gamma PNAs) that possess vastly superior RNA-binding affinity, improved solubility, and favorable biocompatibility. For cellular delivery, we encapsulated the gamma PNAs in poly(lacticco-glycolic acid) (PLGA) nanoparticles (NPs). Our results show that gamma PNAs 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 gamma PNA-treated tumors compared to controls. Overall, our work provides a chemical framework for a novel anti-miR therapeutic approach using gamma PNAs that should facilitate rational design of agents to potently inhibit oncogenic microRNAs.
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