Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 3/15/15 → 1/16/16 |
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