Engineering multimodal nanoparticles to combat triple-negative breast cancer
Date
2025
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of cancer that accounts for about 15-20% of all breast cancer cases and has a poorer short-term prognosis when compared to other subtypes. Many current chemotherapeutics used to treat TNBC are nonspecific, and, therefore, cause off-target effects and fail to elicit a robust tumor response, which results in higher mortality and recurrence rates. Targeted therapy enabled by nanoparticle (NP)-based drug carriers may prove more effective against TNBC. One promising target for TNBC is the Wnt pathway, which is a known developmental pathway that encourages cell proliferation, migration, and cell fate determination and then transitions to mostly stem cell maintenance in adults. Unfortunately, many cancers, including TNBC, have found ways to upregulate the canonical, β-catenin dependent Wnt pathway in order to promote cell proliferation, migration, chemoresistance, and other oncogenic behaviors. Accordingly, Wnt hyperactivity is strongly correlated with recurrence and metastasis. One method to both target and therapeutically manipulate TNBC cells is by coating NPs with antibodies against Frizzled7 (FZD7) receptors in the Wnt pathway, which are overexpressed in ~70% of TNBC cases but minimally expressed by other cells in the body. When antibody nanoconjugates bind FZD7 receptors, it prevents their activation by extracellular Wnt ligands, leading to downstream inhibition of the Wnt signaling pathway. As TNBC lacks targeted treatment options, the ability to use FZD7-targeted NPs to specifically target and eliminate TNBC cells is particularly appealing. This thesis develops methods to coat NPs with FZD7 antibodies and demonstrates their utility in delivering chemotherapeutic agents or small interfering ribonucleic acid (siRNA) therapeutics to TNBC cells. ☐ The first aim of this thesis focused on developing NPs coated with anti-FZD7 antibodies and/or siRNA targeting β-catenin, a downstream protein in the Wnt pathway that is a key mediator in TNBC’s oncogenesis. The goal of this aim was to investigate optimal parameters for modifying the surface of poly(lactic-co-glycolic acid) (PLGA) NPs with either antibodies, siRNA, or both. The second aim of this dissertation investigated the role of FZD7 targeting on the delivery and efficacy of an encapsulated drug, doxorubicin (DOX). The ability of FZD7-targeted, DOX-loaded NPs to inhibit TNBC cell viability was evaluated in vitro and compared against the effects of DOX delivered freely or in non-targeted NPs. Finally, the third aim of this thesis utilized PLGA NPs to carry both FZD7 antibodies and β-catenin siRNAs to inhibit the Wnt pathway in TNBC cells at both the receptor and effector levels. The RNA interference effects of this platform were assessed through in vitro assays that measured TNBC cell viability, migration, drug resistance, and spheroid formation in response to various treatments. ☐ Collectively, this work demonstrates that antibody-modified polymer NPs can be designed to target FZD7 receptors that are overexpressed on TNBC cells and provide specific delivery of diverse therapeutic cargo including chemotherapeutics and siRNAs. Future research in this field should continue to tailor NP design parameters to achieve optimal efficacy and safety and validate therapeutic potential in in vivo models of TNBC.
Description
Keywords
Antibodies, Nanoparticles, Triple-negative breast cancer, Wnt pathway