Primary Human Breast Cancer-Associated Endothelial Cells Favor Interactions with Nanomedicines.

Cancer nanomedicines predominately rely on transport processes controlled by tumor-associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery has been established in animal models, there is a need to probe the translational potential of these findings in human cells. Using primary human breast cancer as a model, we explored and quantified the differential interactions of normal and tumor-associated endothelial cells with clinically relevant nanomedicine formulations. We determined that primary human breast cancer-associated endothelial cells exhibited up to ∼2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. In addition, super-resolution imaging studies revealed a significantly higher intracellular vesicle number for tumor-associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicated the upregulation of transport-related genes, especially motor protein genes, in tumor-associated endothelial cells. Collectively, our results demonstrate that primary human breast cancer-associated endothelial cells exhibit enhanced interactions with nanomedicines. Our findings suggest that these cells potentially play a significant role in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor-associated endothelial cell-mediated transport into human solid tumors may lead to the development of a new class of clinical cancer nanomedicines that are safer and more effective. This article is protected by copyright. All rights reserved.