Grants and Contracts Details
Treatment of Triple Negative Breast Cancer (TNBC) and metastatic breast cancers remain one of the most challenging tasks in clinical oncology. Significant progress has been made towards understanding breast cancer progression at the molecular level, including factors that contribute to tumor growth and metastasis. In addition, several nanodelivery systems that use different materials and physiochemical properties have been pursued. However, effective strategies to block tumor progression and metastasis are still lacking. In this proposal, we will apply the knowledge and technique from the emerging field of RNA nanotechnology to overcome some of the challenges associated with treating TNBC and metastasis. Recently, we have discovered an unusually stable phi29 pRNA three-way junction (3WJ) motif that can be used as a scaffold to construct multivalent RNA nanoparticles with very high chemical and thermodynamic stability. The resulting RNA nanoparticles harbor different siRNA, miRNA, and cancer targeting RNA aptamers that retain 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 8 M urea and do not dissociate at ultra-low concentrations in vitro and in vivo. Systemic injection into the tail-vein of mice has revealed that they remain intact and bind to cancer xenograft specifically and strongly without accumulating in the liver, lungs or other vital organs (Shu D. et al. Nature Nanotechnology, 2011, 6:658). This nanotechnology approach has enhanced the half-life of the RNA nanoparticles by 10-fold compared to bare siRNA. The pRNA-3WJ nanoparticles are non-toxic and display favorable biodistribution, pharmacokinetic profiles, and undetectable immune responses. We have also solved the crystal structure of the pRNA-3WJ motif, which will greatly facilitate the designs of RNA nanoparticles used in this study. The goal of this research project is to construct multivalent RNA nanoparticles, to obtain enhanced or synergistic therapeutic effects for the treatment of TNBC and metastasis. These multivalent particles will include (1) RNA aptamers for targeted binding to TNBC specific cell surface receptors resulting in the internalization of RNA nanoparticles into cancer cells; and (2) Therapeutic modules, such as anti-miRNA to downregulate oncogenic genes and cytotoxic drugs. Emphasis will be on specific tumor targeting and efficiency of gene silencing and chemotherapy animal models. The multiple components carried by the pRNA- 3WJ scaffold would allow for enhanced treatment on cancer cells at low dose regimens, while avoiding nonspecific side effects or induction of host immune responses. The innovative RNA platform will enable us to tackle TNBC phenotypes and metastasis in an unprecedented manner.
|Effective start/end date||3/15/15 → 1/16/16|
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