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Frizzled7 Antibody-Functionalized Nanoshells Enable Multivalent Binding for Wnt Signaling Inhibition in Triple
Rachel S Riley1, Emily S Day1,2,3
1Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, 150 Academy Street, Newark, DE, 19716, USA.
Abstract:
Antibodies that antagonize cell signaling pathways specific to their targeted receptor are invaluable tools to study and treat malignancies, but their utility is limited by high production costs and treatment dosages. Researchers have shown that antibodies conjugated to nanoparticles display increased affinity for their target relative to freely delivered antibodies due to multivalency, and this study investigates how this multivalency can enable antibody-nanoparticle conjugates to inhibit oncogenic cell signaling more effectively than freely delivered antibodies. This effect was evaluated using triple negative breast cancer (TNBC) cells that are characterized by hyperactive Wnt signaling mediated through overexpressed Frizzled7 (FZD7) transmembrane receptors. Through analysis of the expression of β-catenin and Axin2, two downstream targets in the Wnt pathway, the results demonstrate that FZD7 antibody-nanoshell conjugates (FZD7-NS) are drastically more effective at inhibiting Wnt signaling in TNBC cells than freely delivered FZD7 antibodies. Additionally, cells treated with FZD7-NS, but not cells treated with freely delivered FZD7 antibodies, have decreased viability, indicating the therapeutic potential of this technology. The results demonstrate that antibody-functionalized nanoparticles can exploit multivalency for improved signal cascade interference over free antibodies, and this may ultimately permit lower antibody dosages to be administered to study signaling pathways or to manage diseases.
Insights
Antibody-nanoparticle conjugates enhance Wnt signaling inhibition in triple-negative breast cancer cells. This multivalency effect allows for more effective targeting and reduced cell viability compared to free antibodies, suggesting lower therapeutic dosages.
Area of Science:
- Biotechnology
- Oncology
- Nanomedicine
Background:
- Antibodies are crucial for studying and treating malignancies but face limitations due to high costs and dosages.
- Antibody-nanoparticle conjugates offer enhanced target affinity via multivalency.
- Triple-negative breast cancer (TNBC) exhibits hyperactive Wnt signaling due to Frizzled7 (FZD7) overexpression.
Purpose of the Study:
- To investigate if antibody-nanoparticle conjugates can more effectively inhibit oncogenic Wnt signaling than free antibodies.
- To evaluate the therapeutic potential of FZD7 antibody-nanoshell conjugates (FZD7-NS) in TNBC cells.
Main Methods:
- Conjugating FZD7 antibodies to nanoshells to create FZD7-NS.
- Treating TNBC cells with FZD7-NS and free FZD7 antibodies.
- Analyzing downstream Wnt signaling targets (β-catenin and Axin2) expression.
- Assessing cell viability after treatment.
Main Results:
- FZD7-NS significantly inhibited Wnt signaling more effectively than free FZD7 antibodies in TNBC cells.
- Cells treated with FZD7-NS showed decreased viability, unlike those treated with free antibodies.
- Multivalency of antibody-nanoparticle conjugates enhances signal cascade interference.
Conclusions:
- Antibody-functionalized nanoparticles can overcome limitations of free antibodies by exploiting multivalency for improved therapeutic efficacy.
- This approach holds potential for lower antibody dosages in cancer treatment and pathway research.
- FZD7-NS demonstrates therapeutic promise for targeting Wnt-driven TNBC.
