Platinum nanoparticles promote breast cancer cell metastasis by disrupting endothelial barrier and inducing intravasation and extravasation

Abstract

Breast cancer is a common malignancy in women with disappointing prognosis especially the triple-negative subtype. Recently, nanomedicine becomes a promising therapeutic strategy for breast cancer, such as platinum nanoparticles (PtNPs). Despite the promising anticancer effects of PtNPs, the safety of PtNPs remains to be fully evaluated. Herein, a series of cell and animal experiments demonstrate that PtNPs facilitate breast cancer metastasis by damaging the vascular endothelial barrier. PtNPs disrupt endothelial cell proliferation, migration and tube-like structure formation, destruct endothelial adhesions junctions and induce endothelial barrier leakiness in vitro most likely by stimulating intracellular reactive oxygen species (ROS) generation and altering the expression and conformation of endothelial junctional proteins, thus promoting intravasation and extravasation of the implanted 4T1 breast cancer cells and leading to cancer metastasis in female BALB/c nude mice in vivo. In addition, smaller PtNPs (5 nm) are more potent than larger PtNPs (70 nm) in exerting the above effects. The study provides the first evidence that PtNPs can promote breast cancer metastasis by damaging endothelial barrier. The unexpected detrimental effects of PtNPs should be considered in future nanomedicine designs for the treatment of breast cancer.