This project is to organize an interdisciplinary team to work on RNA nanotechnology by constructing polyvalent RNA nanoparticles for specific targeting and delivery to cancer cells. RNA molecules can down-regulate specific gene expression in cancer cells. RNA is particularly attractive as a building block for bottom-up assembly in nanotechnology and nanomedicine. RNA can be manipulated as easily as DNA, but possesses the versatility in structure and function similar to that of proteins. RNA contains single-stranded stem-loops for intra- or inter-RNA interactions which can serve as mounting dovetails, providing advantages over external linking dowels in nanomachine assembly. This CNPP operation comprises of three major functions: the fundamental studies on therapeutic RNA nanoparticle construction; the conjugation and incorporation of therapeutic and targeting moieties to RNA nanoparticles; and the specific delivery of therapeutics to cancer cells. The team includes basic scientists with strong backgrounds in biomedical engineering, chemistry, and RNA and DNA nanotechnology; cancer biologists with extensive experience in ribozyme and siRNA delivery; and pharmaceutical cooperation focusing on RNA therapeutics with expertise in animal trials. The team will elucidate the principles underlying the RNA/RNA interactions in RNA nanoparticle assembly using phi29 motor pRNA system and RNA junction motifs to build polyvalent RNA oligomers containing aptamer, siRNA, ribozyme, ligand, imaging markers or drugs for cancer cell recognition and gene silencing. A new methodology of SELEX will be developed to screen for stable and high affinity RNA aptamers that target and enter cancer cells specifically. Simultaneous delivery and detection will be designed, combining therapy and detection of subsequent therapeutic effects on apoptosis. Approaches of crossover, chemical modification, and cross-linking will be applied to make RNA nanoparticles stable in vivo. Novel fermentation approaches and industry scale production methods will be developed to produce large-scale stable RNA for clinical applications. Animal trials on pharmacokinetics, bio-distribution, toxicity, gene silencing effects, and cancer cell killing will be carried out on animal models of lung cancer, ovarian cancer, liver cancer, and leukemia.
Cancer is a current and long term health care crisis and treatments necessitate the investigation of specific delivery to target cells. This application proposes to fabricate RNA nanoparticles to incorporate therapeutic SiRNA, aptamers, and ribosomes to accomplish targeted delivery. Therapeutic constituents will be selected for the treatment of lung cancer, ovarian cancer, liver cancer, and leukemia.
|Haque, Farzin; Zhang, Hui; Wang, Shaoying et al. (2018) Methods for Single-Molecule Sensing and Detection Using Bacteriophage Phi29 DNA Packaging Motor. Methods Mol Biol 1805:423-450|
|Jasinski, Daniel L; Yin, Hongran; Li, Zhefeng et al. (2018) Hydrophobic Effect from Conjugated Chemicals or Drugs on In Vivo Biodistribution of RNA Nanoparticles. Hum Gene Ther 29:77-86|
|Shu, Yi; Yin, Hongran; Rajabi, Mehdi et al. (2018) RNA-based micelles: A novel platform for paclitaxel loading and delivery. J Control Release 276:17-29|
|Xu, Congcong; Haque, Farzin; Jasinski, Daniel L et al. (2018) Favorable biodistribution, specific targeting and conditional endosomal escape of RNA nanoparticles in cancer therapy. Cancer Lett 414:57-70|
|Jasinski, Daniel L; Li, Hui; Guo, Peixuan (2018) The Effect of Size and Shape of RNA Nanoparticles on Biodistribution. Mol Ther 26:784-792|
|Guo, Sijin; Piao, Xijun; Li, Hui et al. (2018) Methods for construction and characterization of simple or special multifunctional RNA nanoparticles based on the 3WJ of phi29 DNA packaging motor. Methods 143:121-133|
|Haque, Farzin; Xu, Congcong; Jasinski, Daniel L et al. (2017) Using Planar Phi29 pRNA Three-Way Junction to Control Size and Shape of RNA Nanoparticles for Biodistribution Profiling in Mice. Methods Mol Biol 1632:359-380|
|Pi, Fengmei; Zhang, Hui; Li, Hui et al. (2017) RNA nanoparticles harboring annexin A2 aptamer can target ovarian cancer for tumor-specific doxorubicin delivery. Nanomedicine 13:1183-1193|
|Lee, Tae Jin; Yoo, Ji Young; Shu, Dan et al. (2017) RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21. Mol Ther 25:1544-1555|
|Jasinski, Daniel; Haque, Farzin; Binzel, Daniel W et al. (2017) Advancement of the Emerging Field of RNA Nanotechnology. ACS Nano 11:1142-1164|
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