Grants and Contracts per year
Grants and Contracts Details
This project is to organize an interdisciplinary team to work on RNA nanotechnology by constructing polyvalent RNA nanoparticles for specific targeting and delivery to various cancer cell lines. RNA molecules have demonstrated significant potential to down-regulate specific gene expression in cancer cells. The amazing diversities in function and structure make RNA particularly attractive as a building block for bottom-up assembly in nanotechnology and nanomedicine. RNA can be designed and manipulated with a level of simplicity characteristic of DNA, whereas it possesses the versatility in structure and function similar to that of proteins. Typically, RNA contains a large variety of single-stranded stem-loops for intra- and/or inter-molecular interactions with relative low ÄG energy. These loops can serve as mounting dovetails, and thus, external linking dowels might not be needed in nanomachine fabrication and assembly. The CNPP operation is comprised of three major functions: The initial phase of this project is to fully understand the fundamental principles behind therapeutic RNA nanoparticle construction. Intermediate studies will then include conjugating and incorporating therapeutic and targeting moieties to RNA nanoparticles. The translational studies will finally include delivery and apoptosis of cancer cells investigated in cell culture and animal trials. The team includes: 1) basic scientists with strong background in biomedical engineering, chemistry, RNA nanotechnology, and DNA nanotechnology; 2) cancer biologists with extensive experience in ribozyme and siRNA delivery; and 3) pharmaceutical corporations with focus on RNA therapeutics and expertise in animal trials of RNA nanoparticles. The team will elucidate the principles underlying the RNA/RNA interactions in RNA nanoparticle assembly and develop methods for the construction of RNA nanoparticles using the polyvalent phi29 motor pRNA system and RNA junction motifs to build polyvalent RNA dimer, trimer, tetramer, and hexamer constructs containing moieties of aptamer, siRNA, ribozyme, ligand, imaging markers, or drugs for cancer cell recognition and gene silencing. Approaches in DNA nanotechnology will also play an important role in this project and will be imported into the field of RNA nanotechnology. A new methodology of SELEX will be developed to screen for stable and high affinity RNA aptamers that can target and enter cancer cells specifically. Functional groups for simultaneous delivery and detection will also be incorporated into one particle taking advantage of the polyvalent nature of RNA nanoparticles. The particles will be used for both therapy and detection of subsequent therapeutic effects. Approaches of crossover, chemical modification, and cross-linking will be applied to make RNA nanoparticles stable in vivo. Novel fermentation approaches and industrial scale production methods will be develop to produce large-scale stable RNA for clinical applications. Animal trials on pharmacokinetics, bio- distribution, toxicity, gene silencing effect, and cancer cell death will be carried out on animal models of lung cancer, ovarian cancer, liver cancer, and leukemia.
|Effective start/end date||1/16/12 → 1/16/16|
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