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RNA nanoparticles for anti-oncogenic miRNA and drug delivery for cancer therapy

Yin, Hongran
http://rave.ohiolink.edu/etdc/view?acc_num=osu1589836157141191

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Pharmacy.
RNA can serve as powerful building blocks for biotechnological and biomedical applications. A variety of RNA architectures can be constructed via bottom-up self-assembly such as RNA polygons, RNA polyhedrons, RNA dendrimers, etc. The three-way junction (3WJ) motif, derived from packaging RNA (pRNA) of bacteriophage phi29 DNA packaging motor, emerges as a novel and robust delivery platform. The high thermodynamic and chemical stability enables the delivery of therapeutics incorporated to the 3WJ scaffold. In the first study, RNA nanoparticles are functioned with a RNA aptamer binding to CD133 receptor, which is overexpressed in triple negative breast cancer (TNBC), to deliver an 8 nt locked nuclei acid (LNA) sequence for miRNA21 inhibition (anti-miR21). In vitro and in vivo studies revealed that these therapeutic RNA nanoparticles can bind to CD133 positive TNBC cells specifically, upregulate downstream tumor suppressors’ expression efficiently, and reduce the invasive properties of tumor cells effectively. No obvious toxicity or immunogenicity has been detected. Systemic injection of these RNA nanoparticles in animal trial demonstrated high specificity for TNBC tumor targeting and high efficacy for tumor growth inhibition. Besides, 3WJ RNA scaffold is able to accommodate chemical drug Camptothecin (CPT) to improve its water solubility, further specifically target tumor by the incorporation of folic acid (or folate, FA) ligand. In addition to current self-assembly strategies utilizing base paring and RNA tertiary interactions, RNA based micellar nanoparticles are constructed by conjugating a cholesterol molecule onto one helical end of the 3WJ motif. RNA micelles can be assembled by the hydrophobic force, composed of a lipid core and a 3WJ-RNA corona. Our study indicated RNA micelles can deliver therapeutics to tumor and inhibit its growth, while the inclusion of FA as an active targeting ligand in the micelles did not improve the therapeutic efficacy significantly in vivo. The proposed mechanism for micelles’ tumor targeting capability without the need of ligand is due to the size of micelles (~20nm) within the lower end of the nanometer scale that favoring Enhanced Permeability and Retention (EPR) effect. Take advantage of high stability and multivalence, RNA micelles are capable of delivering miRNA, anti-miRNA, siRNA as well as chemical drugs for cancer therapy, especially when targeting ligands are not available. In the third study, the rational design of incorporating siRNA to 3WJ scaffold is exploited. Several factors that may affect Dicer processing of siRNA were investigated, including base pairing length, 3’-overhang and chemical modification. The data provides some hints on the strategy of attaching siRNA to 3WJ motif for efficient processing by Dicer enzyme. To illustrate the processing, 3WJ-siRNA based molecular beacon was built utilizing a pair of fluorophore/quencher. This molecular beacon delivered by FA decorated exosomes, which are developed in our lab as a cytosol delivery vesicle, is able to sense the dynamic siRNA processing intracellularly by monitoring fluorescence signal. In sum, these studies demonstrate the versatile application of RNA nanotechnology and provide the basis for future clinical translation.
Peixuan Guo (Advisor)
Dan Shu (Committee Member)
Sharyn Baker (Committee Member)
Yizhou Dong (Committee Member)
Emanuele Cocucci (Committee Member)
162 p.
Pharmaceuticals

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Citations

  • Yin, H. (2020). RNA nanoparticles for anti-oncogenic miRNA and drug delivery for cancer therapy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1589836157141191

    APA Style (7th edition)

  • Yin, Hongran. RNA nanoparticles for anti-oncogenic miRNA and drug delivery for cancer therapy . 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1589836157141191.

    MLA Style (8th edition)

  • Yin, Hongran. "RNA nanoparticles for anti-oncogenic miRNA and drug delivery for cancer therapy ." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1589836157141191

    Chicago Manual of Style (17th edition)

osu1589836157141191
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This open access ETD is published by The Ohio State University and OhioLINK.