Preparation and evaluation of iRGD-modified PLGA-PEG nanoparticles encapsulating TPEN

This study developed an iRGD-modified PLGA-PEG nanoparticle for targeted delivery of the metal chelator N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). Different from conventional nanoplatforms that rely on exogenous copper delivery to induce cuproptosis, this work focuses on tumor-targeted delivery of TPEN to intervene intracellular metal homeostasis, thereby improving tumor selectivity and reducing systemic risks. The optimized TPEN@1%-iPPN formulation was prepared via co-precipitation, exhibiting a uniform hydrodynamic diameter of 79.85 ± 0.58 nm, narrow size distribution (PDI = 0.160 ± 0.014), and favorable colloidal stability under physiological conditions. Successful encapsulation of TPEN was confirmed by ultraviolet-visible spectroscopy (UV-Vis) and high-performance liquid chromatography (HPLC) quantification, achieving a drug loading of 4.85 ± 0.28% and encapsulation efficiency of 52.20 ± 3.82%. The formulation demonstrated sustained drug release under tumor-mimicking pH 6.5 and enhanced cellular uptake in 4T1 breast cancer cells via iRGD-mediated active targeting. Cytotoxicity assays revealed that TPEN@1%-iPPN possessed significantly greater toxicity against 4T1 cells compared to non-targeted nanoparticles and exhibited reduced off-target effects on normal human umbilical vein endothelial cells (HUVECs), confirming tumor-selective cytotoxicity. This study provides a biocompatible and tumor-selective nanodelivery platform for TPEN, offering a feasible strategy and preliminary experimental foundation for further cuproptosis research.