Journal
MOLECULAR PHARMACEUTICS
Volume 13, Issue 6, Pages 1791-1799Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00933
Keywords
micelles; micelleplexes; miRNAs; miRNA-21; glioblastoma; anti-miRNAs; cell-penetrating peptide
Funding
- Research Facilities Improvement Program Grant from the National Center for Research Resources of the National Institutes of Health (NIH) [C06 RR015482]
- University of Illinois at the Chicago Center for Clinical and Translational Science (CCTS) - NCRR [UL1 TR000050]
- Chicago Biomedical Consortium
- Searle funds at the Chicago Community Trust
- University of Illinois at Chicago Graduate Fellowships
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Glioblastoma multiforme (GBM) and other central nervous system (CNS) cancers have poor long-term prognosis, and there is a significant need for improved treatments. GBM initiation and progression are mediated, in part, by microRNA (miRNA), which are endogenous posttranscriptional gene regulators. Misregulation of miRNAs is a potential target for therapeutic intervention in GBM. In this work, a micelle-like nanoparticle delivery system based upon the block copolymer poly(ethylene glycol-b-lactide-b-arginine) was designed with and without a reducible linkage between the lactide and RNA-binding peptide, R-15, to assess the ability of the micelle-like particles to disassemble. Using confocal live cell imaging, intracellular dissociation was pronounced for the reducible micelleplexes. This dissociation was also supported by higher efficiency in a dual luciferase assay specific for the miRNA of interest, miR-21. Notably, micelleplexes were found to have significantly better stability and higher anti-miRNA activity in cerebrospinal fluid than in human plasma, suggesting an advantage for applying micelleplexes to CNS diseases and in vivo CNS therapeutics. The reducible delivery system was determined to be a promising delivery platform for the treatment of CNS diseases with miRNA therapy.
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