Medical College of Wisconsin
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Dendrimer Gel Nanoparticles with Dual-Targeting of uPAR and Ribonucleotide Reductase R2 Influence Necrosis, Apoptosis, and Cell Cycle Arrest in Triple-Negative Breast Cancer. Mol Pharm 2025 Dec 01;22(12):7620-7629

Date

11/11/2025

Pubmed ID

41217876

Pubmed Central ID

PMC12684374

DOI

10.1021/acs.molpharmaceut.5c01209

Scopus ID

2-s2.0-105023390923 (requires institutional sign-in at Scopus site)   2 Citations

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.

Author List

Chuang HY, Huang YW, Yang H

Author

Hsin-Yin Chuang Postdoctoral Researcher in the Biomedical Engineering department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Cell Cycle Checkpoints
Cell Line, Tumor
Dendrimers
Female
Humans
Mice
Mice, Nude
Nanoparticles
Necrosis
Receptors, Urokinase Plasminogen Activator
Ribonucleoside Diphosphate Reductase
Triple Negative Breast Neoplasms
Xenograft Model Antitumor Assays