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OPTIMIZATION OF NON-VIRAL GENE DELIVERY SYSTEM FOR IMAGE-GUIDED THERAPY FOR TRIPLE NEGATIVE BREAST CANCER

Schilb, Andrew L
http://rave.ohiolink.edu/etdc/view?acc_num=case1627484657204883

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Due to a lack of targeted FDA-approved therapies, current strategies for patients with triple negative breast cancer (TNBC) are with chemotherapeutics. While effective at first, patients tend to relapse and develop metastases with multidrug resistances. RNA interference (RNAi) offers a powerful therapeutic method for inhibiting specific disease targets. MicroRNAs (miRNAs) have great therapeutic promise in TNBC through their ability to target multiple oncogenic pathways. However, these miRNAs therapeutics are limited due to their inefficient delivery to the targeted disease. Thus, RNA therapeutics are dependent on their ability to effectively be delivered to the target tissue. In addition, the success of these therapies can be determined through non-invasive imaging. This research is focused on the synthesis and formulation of a lipid nanoparticle to deliver a small miRNAs to TNBC. To accomplish this, we will convert the previously established solid-phase synthesis of the pH-sensitive amino lipid, ECO, to liquid-phase. ECO is a multifunctional lipid that can self-assemble with genetic material to form nanoparticles that are capable of cytosolic release in the targeted tissue. The resulting lipid nanoparticles are optimized to achieve significant silencing of targeted genes while minimizing cytotoxic effects. Using these optimized nanoparticles, we will deliver a tumor suppressor miRNA and monitor therapeutic efficacy using MR magnetic imaging (MRMI). Within TNBC miR-200c is significantly downregulated and this downregulation has been shown to result in the epithelial to mesenchymal transition (EMT) and cancer stemness. Thus, the overexpression of miR-200c results in the reversal of EMT and the downregulation of the extracellular domain-B fibronectin (EDB-FN). EDB-FN has been reported as an invasive marker for breast cancer cells. In this work, we transfected TNBC with and without drug-resistance with ECO/miR-200c nanoparticles resulting in the upregulation of miR-200c. This resulted in the suppression of invasive, migratory, 3D spheroid formation, and downstream targets with no adverse side effects. The therapeutic efficacy was observed using a contrast agent targeted to EDB-FN, which showed a decrease in contrast-to-noise ratio. This indicated a change in the tumor microenvironment and effective miR-200c delivery. This supports the use of RNAi therapeutics against TNBC as well as use of EDB-FN for therapeutic monitoring using MRMI.
Efstathios Karathanasis, Dr. (Committee Chair)
Zheng-Rong Lu, Dr. (Advisor)
William Schiemann, Dr. (Committee Member)
Agata Exner, Dr. (Committee Member)
173 p.
Biomedical Engineering
nanoparticles; miR-200c; triple negative breast cancer; MRMI; EDB-FN; Drug resistances

Recommended Citations

Citations

  • Schilb, A. L. (2021). OPTIMIZATION OF NON-VIRAL GENE DELIVERY SYSTEM FOR IMAGE-GUIDED THERAPY FOR TRIPLE NEGATIVE BREAST CANCER [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1627484657204883

    APA Style (7th edition)

  • Schilb, Andrew. OPTIMIZATION OF NON-VIRAL GENE DELIVERY SYSTEM FOR IMAGE-GUIDED THERAPY FOR TRIPLE NEGATIVE BREAST CANCER. 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1627484657204883.

    MLA Style (8th edition)

  • Schilb, Andrew. "OPTIMIZATION OF NON-VIRAL GENE DELIVERY SYSTEM FOR IMAGE-GUIDED THERAPY FOR TRIPLE NEGATIVE BREAST CANCER." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1627484657204883

    Chicago Manual of Style (17th edition)

case1627484657204883
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© 2021, some rights reserved.Creative Commons License OPTIMIZATION OF NON-VIRAL GENE DELIVERY SYSTEM FOR IMAGE-GUIDED THERAPY FOR TRIPLE NEGATIVE BREAST CANCER by Andrew L Schilb is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.