Grants and Contracts Details
Systemic toxicity has been a major drawback for chemotherapy and limiting the utility and effectiveness of chemotherapeutics. Noninvasive imaging can be used to monitor the tumor location and targeted drug delivery, thus to provide feedback on the therapeutic process and efficacy of the drugs. Recent advances in applications of nanotechnologies to cancer have led to the development of nanocarriers that can deliver imaging contrast agents and therapeutics at the sub-cellular level. However, clinical translation of nanocarrier-enabled drug delivery faces barriers that are related to variations in formulations and in vivo stability of nanoparticles, and limited data on the fate and toxicity of nanocarriers once they enter the body. Quantitative imaging may help provide quantitative data on nanoparticle behavior and distribution in vivo. Recently, we 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). 2’-Fluoro (2’-F) modification resulted in RNA nanoparticles that were RNase-resistant, while retaining their original folding and biological activities. 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 pRNA-3WJ 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). Our goal is to use this pRNA-3WJ motif to construct ultra-stable RNA nanoparticles carrying multimodal imaging agents and therapeutics for the image-guided targeted delivery to cancer cells. Quantitative imaging methods such as fluorescence imaging and PET imaging will be used to for target characterization (detection, localization, and pathology) of these RNA nanoparticles to study the pharmacokinetics (PK) and pharmacodynamics (PD) of therapeutic uptake and efficacy, respectively, to determine the biodistribution and therapeutic effects across different spatial and functional resolution scales (molecular to organ level).
|Effective start/end date||7/1/14 → 1/16/16|
- National Institute of Biomedical Imaging & Bioengineer: $665,716.00
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