Poster abstracts
Poster number 34 submitted by Dan Shu
Systemic Delivery of Anti-miRNA for Suppression of Triple Negative Breast Cancer Utilizing RNA Nanotechnology
Dan Shu (College of Pharmacy, The Ohio State University), Hui Li (College of Pharmacy, The Ohio State University), Yi Shu (College of Pharmacy, University of Kentucky), Gaofeng Xiong (Department of Molecular and Biomedical Pharmacology, University of Kentucky), Farzin Haque (College of Pharmacy, The Ohio State University), Ren Xu (Department of Molecular and Biomedical Pharmacology, University of Kentucky)
Abstract:
MicroRNAs play important roles in regulating the gene expression and life cycle of cancer cells. In particular, miR-21, an oncogenic miRNA is a major player involved in tumor initiation, progression, invasion and metastasis in several cancers, including triple negative breast cancer (TNBC). However, delivery of therapeutic miRNA or anti-miRNA specifically into cancer cells in vivo without collateral damage to healthy cells remains challenging. We report here the application of RNA nanotechnology for specific and efficient delivery of anti-miR-21 to block the growth of TNBC in orthotropic mouse models. The 15-nm therapeutic RNA nanoparticles contains the phi29 pRNA-3WJ as a core, an anti-miRNA, and the anti-epidermal growth factor receptor (EGFR) aptamer for internalizing RNA nanoparticles into cancer cells via receptor medicated endocytosis. The RNase resistant and thermodynamically stable RNA nanoparticles remained intact after systemic injection into mice and strongly bound to tumors with little or no accumulation in healthy organs eight hours post-injection, and subsequently repressed tumor growth at low doses. The observed specific cancer targeting and tumor regression is a result of several key attributes of RNA nanoparticles: anionic charge which disallows nonspecific passage across negatively charged cell membrane; 'active' targeting using RNA aptamers which increases the homing of RNA nanoparticles to cancer cells; nanoscale size and shape which avoids rapid renal clearance and engulfment by lung macrophages and liver Kupffer cells; favorable biodistribution profiles with little accumulation in healthy organs, which minimizes non-specific side effects; and favorable pharmacokinetic profiles with extended in vivo half-life. The results demonstrate the clinical potentials of RNA nanotechnology based platform to deliver miRNA based therapeutics for cancer treatment.
References:
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2. Shu D, Shu Y, Haque F, Abdelmawla S and Guo P. Thermodynamically stable RNA three-way junction for constructing multifunctional nanoparticles for delivery of therapeutics. Nature Nanotechnology. 2011; 6:658-67.
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4. Shu D, Li H, Shu Y, Xiong G, Haque F, Xu R, Guo P. Systemic Delivery of Anti-miRNA for Suppression of Triple Negative Breast Cancer Utilizing RNA Nanotechnology. ACS Nano. 2015 Oct 27; 9(10):9731-40.
Acknowledgements: The work was supported by NIH grants CA151648 and EB003730 to P.G. and DOD Award No. W81XWH-15-1-0052 to D.S. and R.X.
Keywords: RNA nanotechology, miRNA, RNA aptamer