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.
Recommended Citation
H. Y. Chuang et al., "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 Applied Materials and Interfaces, vol. 17, no. 23, pp. 33439 - 33450, American Chemical Society, Jun 2025.
The definitive version is available at https://doi.org/10.1021/acsami.5c03560
Department(s)
Biological Sciences
Second Department
Chemical and Biochemical Engineering
Keywords and Phrases
activator receptor; confocal microscopy; nanomedicine; ribonucleotide reductase; targeted gene delivery
International Standard Serial Number (ISSN)
1944-8252; 1944-8244
Document Type
Article - Journal
Document Version
Citation
File Type
text
Language(s)
English
Rights
© 2025 American Chemical Society, All rights reserved.
Publication Date
11 Jun 2025
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Biomedical Engineering and Bioengineering Commons, Chemical Engineering Commons
Comments
National Institutes of Health, Grant R01HL140684