CREKA-modified peptide nanoplatform PS/Pep1 enhances ferroptosis and suppresses angiogenesis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) remains an aggressive malignancy with limited targeted therapies, leading to poor patient outcomes. Traditional treatments often struggle with insufficient drug accumulation within tumors and the complex, abnormal tumor vascular microenvironment. Ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy. However, its clinical translation is hampered by challenges in delivering ferroptosis-inducing agents effectively to the tumor site and overcoming the pro-tumorigenic effects of angiogenesis.

Researchers designed a CREKA-modified peptide, Pep1, specifically engineered to actively target fibrin, a key component of the tumor-associated extracellular matrix, to enhance tumor accumulation. This peptide was then integrated into a pH-responsive self-assembling nanoplatform, PS/Pep1. The nanoplatform was designed to undergo a structural transformation from spherical nanoparticles to high aspect ratio aggregates upon exposure to the acidic tumor microenvironment. This transformation was hypothesized to facilitate deeper tumor penetration and sustained local retention, thereby improving intratumoral drug bioavailability. The study evaluated the nanoplatform's ability to induce ferroptosis and suppress angiogenesis, likely in preclinical in vitro and in vivo models, though specific details like dose or animal model are not provided in the abstract.

The PS/Pep1 nanoplatform demonstrated significant improvements in intratumoral drug bioavailability. Mechanistically, it effectively promoted lipid peroxidation within tumor cells, a hallmark of ferroptosis, and simultaneously suppressed the activity of glutathione peroxidase 4 (GPX4), a crucial enzyme that protects cells from oxidative damage and ferroptosis. This dual action led to robust induction of ferroptosis-mediated tumor cell death. Furthermore, PS/Pep1 downregulated the expression of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, thereby suppressing the formation of new blood vessels that support tumor growth. The unique pH-responsive structural transformation of PS/Pep1 from spherical nanoparticles to aggregates with high aspect ratios was confirmed to facilitate deep tumor penetration and sustained local retention, contributing to its enhanced therapeutic efficacy. This synergistic approach of inducing ferroptosis and inhibiting angiogenesis resulted in potent anti-tumor effects.

PS/Pep1 significantly improved intratumoral drug bioavailability, promoted lipid peroxidation, suppressed GPX4 activity, and downregulated VEGF expression, inducing both ferroptosis- and apoptosis-mediated tumor cell death while suppressing angiogenesis.