Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options due to the absence of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2) receptors. We previously developed highly adaptable polyamidoamine (PAMAM) dendrimer-based gel nanoparticles (GDP-uPA/GTI) with dual-targeting capabilities against urokinase-type plasminogen activator receptor (uPAR) and ribonucleotide reductase R2 (R2) to achieve selective antitumor effects. In this study, we investigated the underlying mechanisms of GDP-uPA/GTI-induced tumor inhibition. In vivo, GDP-uPA/GTI significantly downregulated R2 expression and activated caspase 8 and caspase 3, indicating caspase-dependent apoptosis. Histological evaluation of major organs revealed no observable toxicity. In MDA-MB-231 cells, GDP-uPA/GTI induced time-dependent S and G2/M phase cell cycle arrest and significantly increased necrosis, with a moderate rise in apoptotic populations. Compared to naked GTI and nontargeted GDP/GTI, GDP-uPA/GTI consistently showed superior efficacy in R2 knockdown, cell cycle disruption, and apoptosis/necrosis. These findings confirm that GDP-uPA/GTI exerts multilevel antitumor effects through targeted gene suppression, apoptosis induction, and replication blockade and support its continued development as a potent therapeutic strategy for TNBC.
Recommended Citation
H. Y. Chuang et al., "Dendrimer Gel Nanoparticles with Dual-Targeting of UPAR and Ribonucleotide Reductase R2 Influence Necrosis, Apoptosis, and Cell Cycle Arrest in Triple-Negative Breast Cancer," Molecular Pharmaceutics, vol. 22, no. 12, pp. 7620 - 7629, American Chemical Society, Dec 2025.
The definitive version is available at https://doi.org/10.1021/acs.molpharmaceut.5c01209
Department(s)
Biological Sciences
Second Department
Chemical and Biochemical Engineering
Keywords and Phrases
apoptosis; cell cycle arrest; nanomedicine; ribonucleotide reductase; targeted gene delivery; urokinase-type plasminogen activator receptor
International Standard Serial Number (ISSN)
1543-8392; 1543-8384
Document Type
Article - Journal
Document Version
Citation
File Type
text
Language(s)
English
Rights
© 2025 American Chemical Society, All rights reserved.
Publication Date
01 Dec 2025
PubMed ID
41217876
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Biomedical Engineering and Bioengineering Commons, Chemical Engineering Commons
Comments
Missouri University of Science and Technology, Grant R01HL140684