Grants and Contracts Details
Guo lab recently discovered a phi29 pRNA three-way junction (3WJ) motif with unusual thermodynamic stability that was used as a RNA scaffold to construct bi-, tri-, and tetra-valent RNA nanoparticles with very high chemical and thermodynamic stability (Nature Nanotechnology, 2011, 6:658-67; Nano Today, 2012, 7:245-257). The resulting RNA nanoparticles harboring different functional modules retained their folding and independent functionalities for specific cell binding, gene silencing, catalytic function, and cancer targeting both in vitro and in vivo. These RNA nanoparticles are resistant to denaturation in 8M urea and, do not dissociate at ultra-low concentrations in vitro and, in vivo. Systemic injection into the tail-vein of mice revealed that they remained intact and strongly bound to cancers without entering liver, lung or other vital organs. The 3WJpRNA- based RNA nanoparticles displayed favorable pharmacological profiles including biodistribution, pharmacokinetics (stability, half-life and clearance rate), undetectable immune responses and toxicity (Molecular Therapy, 2011, 19:1312-22). In this proposal, Guo lab will focus on: (1) constructing 3WJ-pRNA nanoparticles harboring exosomal miR17 and miR155; (2) evaluating the inter-molecular assembly process of the RNA fragments by determining TM, ÄG (Gibbs Free Energy), ÄH (Enthalpy), and ÄS (Entropy); (3) determining dissociation conditions using competition assays; (4) characterizing the size and shape of exosomal RNA nanoparticles with AFM (Atomic force microscopy); (5) conduct FRET (Fluorescence resonance energy transfer) assays to test the stability of EPNVm17 and EPNVm155; and (6) assessing the pharmacokinetic (PK) and biodistribution profiles of 3WJpRNA nanoparticles harboring exosomal miRNA/ncRNA in mouse model. Key PK parameters include: t1/2 (half-life), AUC (Area Under Curve), Vd (Volume of Distribution), C0 (Concentration at Time zero), CL (Clearance), and MRT (Mean Residence Time).
|Effective start/end date||8/1/14 → 7/31/15|
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