Human Breast Tumor-associated Endothelial Cells Favor Interactions with Nanomedicines

Nanomedicines, designed to improve the effectiveness of cancer treatment, have not met anticipated outcomes owing to suboptimal delivery efficiency to tumors. While the enhanced permeability and retention (EPR) effect has been explored, recent research challenges the predominant passive accumulation theory. This study explores the mechanisms governing nanoparticle entry into tumors by comparing human breast tumor-associated endothelial cells (HBTECs) and healthy human mammary macrovascular endothelial cells (HMMECs). Our results demonstrate that HBTECs exhibit higher nanoparticle uptake, involving three major endocytic pathways. Gene expression analysis reveals the upregulation of transport-related genes, especially motor protein genes, in tumor-associated endothelial cells. These insights highlight the need for comprehensive investigations into nanoparticle transport mechanisms and associated factors within the tumor microenvironment, essential for advancing drug delivery and therapeutic outcomes. To investigate the difference in nanoparticle interactions with endothelial cells from tumor and healthy tissues, we employed two primary human cell types: human breast tumor-associated endothelial cells (HBTECs) and human mammary microvascular endothelial cells (HMMECs). Two experimental conditions, one without and one with gold nanoparticle incubation, were applied. Consequently, we established four distinct groups: HBTEC, HMMEC, HBTEC_Au (HBTECs with gold nanoparticle incubation), and HMMEC_Au (HMMECs with gold nanoparticle incubation). RNA-seq was conducted on these groups. For the RNA-seq result analysis, the four groups were compared in a pairwise manner, which are HBTEC vs HMMEC, HBTEC_Au vs HMMEC_Au, HBTEC_Au vs HBTEC, and HMMEC_Au vs HMMEC, to explore the impact of both cell origin differences and nanoparticle incubation.