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Highly Adaptable Dendrimer Gel Nanoparticles with Dual Targeting of uPAR and Ribonucleotide Reductase R2 for Better Retention and Improved Therapeutic Outcomes in Triple-Negative Breast Cancer. ACS Appl Mater Interfaces 2025 Jun 11;17(23):33439-33450

Date

06/03/2025

Pubmed ID

40456699

Pubmed Central ID

PMC12700075

DOI

10.1021/acsami.5c03560

Scopus ID

2-s2.0-105007512700 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancers and lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to hormonal or anti-HER2 therapies. Due to its poor prognosis and limited treatment options, there is an urgent need for targeted therapies. In this study, we developed highly adaptable polyamidoamine (PAMAM) dendrimer-based gel nanoparticles with dual-targeting capabilities against urokinase-type plasminogen activator receptor (uPAR) and ribonucleotide reductase R2 (R2). These nanoparticles were designed to target both TNBC cells and cancer-associated stromal cells by leveraging uPA-uPAR interactions and delivering the antisense oligonucleotide GTI-2040 (GTI) against R2. The resulting dual-functional dendrimer gel nanoparticles, GDP-uPA/GTI, demonstrated good biocompatibility, with an average size of ∼16.45 nm. GDP-uPA/GTI enhanced GTI delivery by 3.4-fold in TNBC cells (MDA-MB-231) and by 4.8-fold in stromal cells (HCC2218) compared to GTI alone. It reduced R2 expression by 83.1% and induced ∼30% TNBC cell death. In a TNBC xenograft model, GDP-uPA/GTI significantly inhibited tumor growth by 50.5%. These findings highlight the unique design of the dual-functional dendrimer gel nanoparticles and their dual-targeting efficacy, demonstrating their potential as a promising therapeutic strategy for TNBC.

Author List

Chuang HY, Huang D, Qi L, Singh V, Chernatynskaya A, Huang YW, Yang H

Authors

Hsin-Yin Chuang Postdoctoral Researcher in the Biomedical Engineering department at Medical College of Wisconsin
Hu Yang PhD Chair, Professor in the Biomedical Engineering department at Medical College of Wisconsin




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

Animals
Antineoplastic Agents
Cell Line, Tumor
Dendrimers
Female
Gels
Humans
Mice
Mice, Nude
Nanoparticles
Receptors, Urokinase Plasminogen Activator
Ribonucleotide Reductases
Triple Negative Breast Neoplasms
Xenograft Model Antitumor Assays