Nanoparticle-mediated delivery of antibodies and/or RNA for gene regulation in triple-negative breast cancer
Date
2022
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease that is unsusceptible to most current targeted or hormonal therapies because it lacks expression of the three receptors these therapies target: the estrogen, progesterone, and human epidermal growth factor 2. Consequently, patients with TNBC suffer from earlier relapse, increased rates of metastasis, and lower survival rates than patients with other forms of breast cancer. New treatment strategies must be developed to improve the prognosis for TNBC patients, and the research described here seeks to meet this need through targeted gene regulation. TNBC progression is driven by both loss of expression of the tumor suppressive microRNA miR-34a and by overactivity of the Wnt signaling pathway, which appears in the form of elevated Frizzled7 receptor expression and elevated β-catenin protein expression. The aberrant expression of miR-34a, Frizzled7, and β-catenin leads to increased translation of numerous oncogenes that are downstream of these molecules. Hence, increasing miR-34a expression through the delivery of miRNA mimics or decreasing β-catenin expression through delivery of small interfering RNAs (siRNAs) would profoundly impair TNBC progression. Unfortunately, naked RNA molecules cannot be used therapeutically because they are unstable in biological fluids, exhibit unfavorable pharmacokinetics, and cannot passively enter cells. To overcome these issues, various nanocarriers have been designed to protect RNAs from degradation and deliver them into target cells to initiate gene regulation. However, most reported systems lack specificity, leading to off-target effects. This dissertation addresses the need for selective gene regulation by developing two different NP platforms that use photoactivation or antibody targeting to provide TNBC cell-specific gene regulation. The first platform uses light-responsive nanoparticles called nanoshells (NS) as a carrier for miR-34a mimics. Chapter 3 demonstrates that these conjugates can hold the miRNA inactive until it is released from the NS surface on-demand with light activation. The second platform consists of NS coated with β-catenin siRNA molecules and Frizzled7 antibodies. Here, the antibodies both target TNBC cells and block Wnt ligand/Frizzled7 receptor interactions to suppress the signaling pathway at both the receptor and effector level. Chapter 4 examines the effectiveness of these Wnt inhibitory siRNA/antibody nanocarriers in vitro, while Chapter 5 demonstrates their utility in vivo. This research is both innovative and impactful because it develops and validates two distinct nanocarrier platforms to treat TNBC through high precision gene regulation. With further development, these and other RNA nanocarrier platforms have substantial potential to transform TNBC patient care.
Description
Keywords
Antibody targeting, MicroRNA, Nanoshells, Nanotechnology, RNA interference, siRNA