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Highly Adaptable Dendrimer Gel Nanoparticles with Dual Targeting of uPAR and Ribonucleotide Reductase R2 for Better
Hsin-Yin Chuang1,2, Da Huang2,3, Lin Qi2
1Department of Biological Sciences, Missouri University of Science and Technology, Rolla, Missouri 65409, United States.
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.
Insights
New dual-targeting nanoparticles effectively deliver therapies to triple-negative breast cancer (TNBC) cells and surrounding stromal cells. This innovative approach shows significant potential for treating TNBC, a challenging cancer with limited options.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapy options due to absent estrogen receptor (ER), progesterone receptor (PR), and HER2.
- Urgent need exists for novel therapeutic strategies to improve TNBC prognosis.
Purpose of the Study:
- To develop adaptable polyamidoamine (PAMAM) dendrimer-based gel nanoparticles for dual-targeting TNBC.
- To investigate the efficacy of these nanoparticles in delivering GTI-2040 (GTI) antisense oligonucleotide against ribonucleotide reductase R2 (R2).
Main Methods:
- Created dual-functional dendrimer gel nanoparticles (GDP-uPA/GTI) targeting urokinase-type plasminogen activator receptor (uPAR) and R2.
- Evaluated nanoparticle biocompatibility, size, and drug delivery enhancement in TNBC and stromal cells.
- Assessed R2 expression reduction, TNBC cell death, and tumor growth inhibition in a TNBC xenograft model.
Main Results:
- GDP-uPA/GTI nanoparticles exhibited good biocompatibility with an average size of ~16.45 nm.
- Enhanced GTI delivery by 3.4-fold in TNBC cells and 4.8-fold in stromal cells.
- Achieved 83.1% R2 expression reduction, ~30% TNBC cell death, and 50.5% tumor growth inhibition in vivo.
Conclusions:
- Dual-functional dendrimer gel nanoparticles demonstrate effective dual-targeting capabilities for TNBC.
- This novel therapeutic strategy holds promise for improving TNBC treatment outcomes.
