Poster abstracts
Poster number 46 submitted by Zhefeng Li
Thermodynamically Stable RNA Nanoparticles for Cancer Targeting
Farzin Haque, Dan Shu, Hui, Li, Daniel Jasinski (College of Pharmacy; College of Medicine/Department of Physiology Cell Biology/Dorothy M. Davis Heart and Lung Research Institute), Zhefeng Li (College of Pharmacy; College of Medicine/Department of Physiology Cell Biology/Dorothy M. Davis Heart and Lung Research Institute), Peixuan Guo (College of Pharmacy; College of Medicine/Department of Physiology Cell Biology/Dorothy M. Davis Heart and Lung Research Institute), Tae Jin Lee, Carlo Croce (Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center; The Ohio State University, Columbus, OH, 43210, USA;), Yi Shu, Emil Khisamutdinov, Ashwani Sharma, (Nanobiotechnology Center, 4Department of Pharmaceutical Sciences, Markey Cancer Center; University of Kentucky, Lexington, KY 40536, USA), Piotr Rychahou, B. Mark Evers (Nanobiotechnology Center, Markey Cancer Center; Department of Surgery; University of Kentucky, Lexington, KY 40536, USA.)
Abstract:
RNA nanotechnology encompasses the use of RNA as a construction material to build homogeneous nanostructures by bottom-up self-assembly with defined size, structure, and stoichiometry; this pioneering concept first demonstrated in 1998 has now created an unexpected paradigm of materials engineering and synthetic structural biology. Our platform is based on the packaging RNA (pRNA) of bacteriophage phi29 DNA packaging motor. The pRNA is a versatile molecule and possesses three structural features which has been used for constructing multivalent 3D architectures with diverse sizes and shapes: loop-loop (hand-in-hand) interactions; palindrome sequences (foot-foot-interactions); and three-way junction motif. These RNA nanoparticles are thermodynamically stable, resistant to RNase degradation, and can harbor resourceful functionalities for therapeutic applications. All incorporated functional modules, such as siRNA, ribozymes, aptamers, miRNAs, anti-miRNAs and other functionalities, folded correctly and functioned independently within the nanoparticles. The incorporation of all functionalities was achieved prior, but not subsequent, to the assembly of the RNA nanoparticles, thus ensuring the production of homogeneous therapeutic nanoparticles. More importantly, upon systemic injection, these RNA nanoparticles targeted varieties of cancer xenografts and metastatic cells exclusively in vivo with little or no accumulation in healthy vital organs and tissues. The observed specific cancer targeting is a result of several key attributes of RNA nanoparticles: anionic charge which disallows nonspecific passage across negatively charged cell membrane; 'active' targeting using RNA aptamers or chemical ligands which increases the homing of RNA nanoparticles to cancer cells; nanoscale size and shape which avoids rapid renal clearance and engulfment by lung macrophages and liver Kupffer cells; favorable biodistribution profiles with little accumulation in healthy organs, which minimizes non-specific side effects; and favorable pharmacokinetic profiles with extended in vivo half-life, non-induction of interferon and cytokine responses. The results demonstrate the clinical potentials of RNA nanotechnology based platform for cancer targeting.
References:
1. Guo, P., C. Zhang, Chen, C., K. Garver, M. Trottier and C. Chen. 1998. Molecular Cell 2:149.
2. Guo P. Nature Nanotechnology. 2010. 5:833.
3. Guo, P., S. Erickson, and D. Anderson. Science. 1987. 236:690.
4. Shu D, Shu Y, Haque F, Guo P. Nature Nanotechnology. 2011. 6:658.
5. Haque F, Shu D, Shu Y, Rychahou PG, Evers BM, Guo P. Nano Today. 2012. 7:245.
6. Shu Y, Haque F, Shu D, Li W, Zhu Z, Kotb M, Lyubchenko Y, Guo P. RNA. 2013. 19:767.
7. Lee TJ et. al., Guo P, Croce CM. Oncotarget. 2015).
8. Rychahou P, et al, Guo P, Evers BM. ACS Nano. 9:1108.
9. Khisamutdinov EF, Li H, Jasinski DL, Chen J, Fu J, Guo P. Nucleic Acids Res. 2014. 42:9996.
10. Jasinski DL, Khisamutdinov EF, Lyubchenko YL, Guo P. ACS Nano. 2014. 8:7620.
11. Khisamutdinov EF, Jasinski DL, Guo P. ACS Nano. 2014. 8:4771.
Keywords: RNA nanotechnology, Cancer targeting, pRNA