Titanium Dioxide Nanoparticles Enhance Leakiness and Drug Permeability in Primary Human Hepatic Sinusoidal Endothelial Cells.

Jie Tee,Hannah Koh,David Leong,Han Ho,Li Ng

doi:10.3390/ijms20010035

Abstract

Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the blood compartment from the hepatic cells, regulating hepatic vascular tone and portal pressure amidst changes in the blood flow. In the presence of pathological conditions, phenotypic changes in LSECs contribute to the progression of chronic liver diseases, including the loss of endothelial permeability. Therefore, modulating LSECs offers a possible way to restore sinusoidal permeability and thereby improve hepatic recovery. Herein, we showed that titanium dioxide nanoparticles (TiO2 NPs) could induce transient leakiness in primary human hepatic sinusoidal endothelial cells (HHSECs). Interestingly, HHSECs exposed to these NPs exhibited reduced protein kinase B (Akt) phosphorylation, an important protein kinase which regulates cell attachment. Using a 3D co-culture system, we demonstrated that TiO2 NPs diminished the attachment of HHSECs onto normal human hepatic cell LO2. To further illustrate the significance of leakiness in liver sinusoids, we showed that NP-induced leakiness promoted Sunitinib transport across the HHSEC layer, resulting in increased drug uptake and efficacy. Hence, TiO2 NPs have the potential to modulate endothelial permeability within the specialized sinusoidal endothelium, especially during events of fibrosis and occlusion. This study highlighted the possible use of inorganic NPs as a novel strategy to promote drug delivery targeting the diseased liver.

Highlights

The liver is a vital organ involved in homeostasis through the metabolism of biomolecules and xenobiotics, regulation of blood glucose, bile production and excretion of bilirubin
This NP-induced leakiness required the presence of human hepatic sinusoidal endothelial cells (HHSECs) as we showed that there was no increase in leakiness in the insert with only the extracellular matrix (ECM) coating, which further suggested that the ECM layer barrier was compromised by the endothelial cells
We showed that TiO2 NPs could induce transient endothelial leakiness in liver sinusoids using HHSECs as the endothelial cell model

Summary

Introduction

The liver is a vital organ involved in homeostasis through the metabolism of biomolecules and xenobiotics, regulation of blood glucose, bile production and excretion of bilirubin. With high exposure to circulating endotoxins and antigens from the gut, the liver plays a central role in the immunological response to remove toxic agents from the bloodstream [1] These functions are supported by the presence of discontinuous sinusoids formed by fenestrated endothelium with intercellular gaps and fragmented basement membrane to facilitate the bidirectional transport of cells and molecules across the sinusoidal barrier [2]. Liver sinusoidal endothelial cells (LSECs) are highly specialised cells that constitute the permeable barrier between the blood and liver parenchyma [3] Under physiological conditions, they help to maintain portal pressure by regulating hepatic vascular tone and contribute to hepatic stellate cell (HSC) quiescence, thereby inhibiting fibrogenesis and intrahepatic vasoconstriction. Portal hypertension and hepatic dysfunction ensue as the major consequences of liver cirrhosis [8]

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