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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151648-02
Application #
8133975
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M1))
Program Officer
Morris, Stephanie A
Project Start
2010-08-25
Project End
2012-01-15
Budget Start
2011-08-01
Budget End
2012-01-15
Support Year
2
Fiscal Year
2011
Total Cost
$78,456
Indirect Cost
Name
University of Cincinnati
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Jasinski, Daniel; Haque, Farzin; Binzel, Daniel W et al. (2017) Advancement of the Emerging Field of RNA Nanotechnology. ACS Nano 11:1142-1164
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
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
Pi, Fengmei; Zhao, Zhengyi; Chelikani, Venkata et al. (2016) Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism. J Virol 90:8036-46
Khisamutdinov, Emil F; Jasinski, Daniel L; Li, Hui et al. (2016) Fabrication of RNA 3D Nanoprisms for Loading and Protection of Small RNAs and Model Drugs. Adv Mater 28:10079-10087
Sharma, Ashwani; Haque, Farzin; Pi, Fengmei et al. (2016) Controllable self-assembly of RNA dendrimers. Nanomedicine 12:835-844
Pi, Fengmei; Vieweger, Mario; Zhao, Zhengyi et al. (2016) Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors. Expert Opin Drug Deliv 13:23-36
Guo, Peixuan; Noji, Hiroyuki; Yengo, Christopher M et al. (2016) Biological Nanomotors with a Revolution, Linear, or Rotation Motion Mechanism. Microbiol Mol Biol Rev 80:161-86
Binzel, Daniel W; Shu, Yi; Li, Hui et al. (2016) Specific Delivery of MiRNA for High Efficient Inhibition of Prostate Cancer by RNA Nanotechnology. Mol Ther 24:1267-77
Binzel, Daniel W; Khisamutdinov, Emil; Vieweger, Mario et al. (2016) Mechanism of three-component collision to produce ultrastable pRNA three-way junction of Phi29 DNA-packaging motor by kinetic assessment. RNA 22:1710-1718

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