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 is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor-associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer-associated endothelial cells exhibit up to ≈2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super-resolution imaging studies reveal 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 indicate the upregulation of transport-related genes, especially motor protein genes, in tumor-associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer-associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cells 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 safer and more effective clinical cancer nanomedicines.

Gold Nanoparticles Inhibit Macropinocytosis by Decreasing KRAS Activation.

The RAS-transformed cells utilize macropinocytosis to acquire amino acids to support their uncontrolled growth. However, targeting RAS to inhibit macropinocytosis remains a challenge. Here, we report that gold nanoparticles (GNP) inhibit macropinocytosis by decreasing KRAS activation. Using surface-modified and unmodified GNP, we showed that unmodified GNP specifically sequestered both wild-type and mutant KRAS and inhibited its activation, irrespective of growth factor stimulation, while surface-passivated GNP had no effect. Alteration of KRAS activation is reflected on downstream signaling cascades, macropinocytosis and tumor cell growth in vitro, and two independent preclinical human xenograft models of pancreatic cancer in vivo. The current study demonstrates NP-mediated inhibition of macropinocytosis and KRAS activation and provides translational opportunities to inhibit tumor growth in a number of cancers where activation of KRAS plays a major role.

Surface Chemistry- and Intracellular Trafficking-Dependent Autophagy Induction by Iron Oxide Nanoparticles.

Autophagy is a cellular self-clearance process for maintaining regular cytoplasmic function, and modulation of autophagy can influence cytotoxicity, apoptosis, and clearance of toxic amyloid fibril. In a recent work, functional nanoparticles are used to modulate autophagy. However, the role of nanoparticle uptake mechanisms and their intracellular processing on autophagy is vaguely understood. Here, we show that autophagy is influenced by nanoparticle surface chemistry-directed intracellular trafficking and localization. In particular, we have designed iron oxide nanoparticles functionalized with arginine/arginine methyl ester/octyl/oleyl/cholesterol with a high cell uptake property. We found that autophagy is induced by octyl/oleyl functionalization without appreciable cell death. Further study shows that enhanced cytosolic delivery over membrane localization and increased intracellular aggregation over homogeneous cytosolic distribution lead to autophagy induction via intracellular reactive oxygen species generation. The observed result can be used to design functional nanoparticles/nanodrugs for modulating cellular autophagy that can be used in various biomedical applications.