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A Microenvironment-Driven Peptide Nanoplatform Enhances Ferroptosis and Antiangiogenic Activity for Triple-Negative
Yuanyuan Chen1, Yun Liu2, Xiumei Sun3
1College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang261053, China.
Abstract:
Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive nature and limited therapeutic options. Among emerging therapeutic approaches, ferroptosis induction has attracted increasing attention due to its unique mode of action; however, its efficacy is often restricted by insufficient intratumoral drug accumulation and the abnormal tumor vascular microenvironment. Here, we designed a CREKA-modified peptide, Pep1, to actively target tumor-associated fibrin and increase accumulation in the tumor and further developed a pH-responsive self-assembling nanoplatform, PS/Pep1. PS/Pep1 significantly improved intratumoral drug bioavailability, promoted lipid peroxidation, suppressed glutathione peroxidase 4 (GPX4) activity, and downregulated vascular endothelial growth factor (VEGF) expression, thereby inducing ferroptosis- and apoptosis-mediated tumor cell death while suppressing angiogenesis. Upon exposure to the acidic tumor microenvironment, PS/Pep1 transformed from spherical nanoparticles into aggregates with high aspect ratios, facilitating deep tumor penetration and sustained local retention. In summary, this study presents a smart nanomedicine strategy that integrates active targeting, microenvironment-responsive structural transformation, and the synergistic regulation of ferroptosis-mediated cell death and angiogenesis, providing a promising therapeutic paradigm for TNBC treatment.
Insights
This study developed a smart nanomedicine (PS/Pep1) that targets triple-negative breast cancer (TNBC). It effectively induces cancer cell death by promoting ferroptosis and apoptosis while inhibiting tumor growth and blood vessel formation.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Oncology
Background:
- Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and limited treatment options.
- Current ferroptosis induction strategies for TNBC face limitations including poor drug accumulation and an unfavorable tumor microenvironment.
Purpose of the Study:
- To design and develop a novel pH-responsive, peptide-modified nanoplatform (PS/Pep1) for enhanced TNBC therapy.
- To investigate the potential of PS/Pep1 to improve intratumoral drug delivery, induce ferroptosis and apoptosis, and suppress angiogenesis in TNBC.
Main Methods:
- Engineered a CREKA-modified peptide (Pep1) for active targeting of tumor-associated fibrin.
- Developed a pH-responsive, self-assembling nanoplatform (PS/Pep1) that transforms in acidic tumor microenvironments.
- Evaluated PS/Pep1's effects on drug bioavailability, lipid peroxidation, glutathione peroxidase 4 (GPX4) activity, vascular endothelial growth factor (VEGF) expression, and tumor cell death.
Main Results:
- PS/Pep1 demonstrated enhanced intratumoral drug accumulation and improved bioavailability.
- The nanoplatform effectively promoted lipid peroxidation, suppressed GPX4 activity, and downregulated VEGF expression.
- PS/Pep1 induced both ferroptosis and apoptosis, leading to tumor cell death and suppressed angiogenesis, with structural transformation enhancing tumor penetration.
Conclusions:
- The developed PS/Pep1 nanomedicine represents a promising strategy for TNBC treatment by integrating active targeting and microenvironment responsiveness.
- This approach synergistically enhances ferroptosis-mediated cell death and inhibits angiogenesis, offering a novel therapeutic paradigm for aggressive TNBC.
