Ultrastable Nontoxic RNA Nanoparticles for Targeting Triple-Negative Breast Cancer Stem Cells
Abstract
Clinical studies have shown that triple negative breast cancers (TNBC) are the most aggressive breast cancer sub-type and TNBC patients are frequently faced with poor prognosis and high mortality. Thus, the development of targeted therapies for TNBCs is urgently and critically needed for this patient population. We have successfully designed non-toxic and non-immunogenic RNA nano-architectures capable of penetrating across heterogeneous biological barriers to selectively target TNBC cells in mice after systemic injection with little accumulation in normal organs and tissues. This represents a significant breakthrough and has immense potential to transform TNBC treatment. Overarching Challenges to Be Addressed: (1) Revolutionize treatment regimens by replacing drugs that have life-threatening toxicities with safe, effective interventions. (2) Identify what drives breast cancer growth; determine how to stop it. Rationale/Objective/Aims: While the underlying biological mechanisms of TNBC have been unraveled to a large extent over the last decade, effective strategies to deliver therapeutics to cancer cells in vivo has remained a great challenge. We recently discovered a phi29 pRNA three-way junction (3WJ) motif with unusually robust properties that can be used as a scaffold to construct a new generation of drugs composed purely of RNA. Our goal is to apply our innovative non-toxic and non-immunogenic RNA constructs with specific TNBC targeting capability to deliver high doses of therapeutic payloads to the cancer cells with little or no collateral damage to healthy tissues. To achieve this goal, several functional modules will be incorporated into our multivalent ultrastable RNA platform: (1) imaging module for visualizing the tumor non-invasively in vivo; (2) RNA probes for targeting to breast cancer-specific cell surface markers; and (3) therapeutic drugs, such as RNA interference modules to specifically downregulate genes involved in cancer progression and metastasis program. We will establish several orthotopic mouse models to systematically evaluate the RNA constructs and validate their anti-proliferative, anti-invasive, and anti-metastasis properties. Translational Relevance and Ultimate Applicability: In the vast majority of patients, it is not the primary tumor, but relapse and metastasis to distant sites that are the main cause of death. Our research findings will primarily help patients who (1) develop intrinsic or acquired resistance to commonly used chemotherapeutic drugs and (2) develop metastasis in vital organs (lungs, liver, bone, and lymph nodes) arising from primary tumors in the breast. Our RNA nanotechnology approach has several advantages over traditional methods: improved drug (anti-miRNA) formulations with increased plasma solubility and prolonged drug half-life, targeted delivery, and drug release specifically in the cancer cells, which can maximize antitumor activity while significantly minimizing non-specific toxicity of these drugs. As a result, the chances of the patient surviving from TNBC will be significantly increased coupled with substantial improvement in the patient s quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510052
Entities
People
- Dan Shu
Organizations
- United States Army
- University of Kentucky