The Delivery of Small Interfering RNA to Hepatic Stellate Cells Using a Lipid Nanoparticle Composed of a Vitamin A-Scaffold Lipid-Like Material

Baek

et al. 2021

In Vivo

Background/Aim: The pathological role of vascular endothelial growth factor receptor 2 (VEGFR-2) in chronic liver injury and liver regeneration is not fully understood. This study analysed the role of VEGFR-2 in liver fibrosis and its regeneration process. Materials and Methods: We administered intraperitoneally 50 mg/kg to 300 mg/kg thioacetamide (TAA) to 9-week-old male mice for 17 weeks. We measured levels of VEGFR-2 protein and identified the location of cells that specifically express VEGFR-2. Results: VEGFR-2 is rarely expressed in normal hepatocytes. However, high VEGFR-2 expression in liver sinusoidal endothelial cells was noted in the TAA group. Conversely, the group that experienced regeneration from liver fibrosis showed significantly higher VEGFR-2 expression in the nucleus of hepatocytes compared to the other groups. Conclusion: VEGFR-2 plays a pivotal role in the nucleus of hepatocytes during liver regeneration and VEGFR-2 may be closely related to cell division. Therefore, VEGFR-2 may be a new therapeutic target for liver regeneration.Liver fibrosis is marked by the formation of an abnormally large amount of scar tissue in the liver (1). Liver fibrosis represents the final common route of chronic liver disease, which eventually leads to cirrhosis (2). Chronic liver disease and cirrhosis result in approximately 35,000 deaths yearly in the United States and cirrhosis is the ninth leading cause of death (3). Therefore, it is very important that liver fibrosis does not progress to cirrhosis, an irreversible stage.Angiogenesis, which is the process of new blood vessel growth from existing vessels, is essential for the physiological functioning of tissues (4). Hepatic angiogenesis is closely associated with the progression of fibrosis in chronic liver diseases (5). According to a recent study, hepatic angiogenesis occurs in chronic liver disease, and is characterized by progressive fibrosis (6). Angiogenesis is a dynamic process regulated by the balance between pro-angiogenic and antiangiogenic factors. Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors (4).Hepatocytes play a key role in angiogenesis, and have a close anatomical relationship with endothelial cells that secrete VEGF (7). VEGF regulates blood and lymphatic vessel development and maintains homeostasis (8). VEGF is primarily produced by endothelial cells in response to hypoxia and by stimulation of growth factors such as transforming growth factor, interleukins or platelet derived growth factor (9, 10). The biological function of VEGF is mediated upon binding to type III receptor tyrosine kinase (RTK), VEGF receptor 1 (VEGFR-1, Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4) (11,12). VEGF stimulates angiogenesis by 1473 This article is freely accessible online.

Section: Discussionmentioning

confidence: 99%

Nuclear VEGFR-2 Expression of Hepatocytes Is Involved in Hepatocyte Proliferation and Liver Regeneration During Chronic Liver Injury

Baek

et al. 2021

In Vivo

“…NP delivery to the HSCs has been one of the most important issues for the treatment of chronic liver fibrosis [34,35,36], a condition induced by the activation of HSCs and their transformation to a myofibroblast-producing collagen-rich extracellular matrix, resulting in severe disruption of the liver architecture. Kupffer cells, LSECs, and a collagenous extracellular matrix have been insurmountable obstacles for NP or drug delivery to HSCs to treat liver fibrosis, despite several studies on this issue [33].…”

Section: Discussionmentioning

confidence: 99%

Hepatic Cellular Distribution of Silica Nanoparticles by Surface Energy Modification

Nam

et al. 2019

IJMS

The cellular distribution of silica nanoparticles (NPs) in the liver is not well understood. Targeting specific cells is one of the most important issues in NP-based drug delivery to improve delivery efficacy. In this context, the present study analyzed the relative cellular distribution pattern of silica NPs in the liver, and the effect of surface energy modification on NPs. Hydrophobic NP surface modification enhanced NP delivery to the liver and liver sinusoid fFendothelial cells (LSECs). Conversely, hydrophilic NP surface modification was commensurate with targeting hepatic stellate cells (HSCs) rather than other cell types. There was no notable difference in NP delivery to Kupffer cells or hepatocytes, regardless of hydrophilic or hydrophobic NP surface modification, suggesting that both the targeting of hepatocytes and evasion of phagocytosis by Kupffer cells are not associated with surface energy modification of silica NPs. This study provides useful information to target specific cell types using silica NPs, as well as to understand the relationship between NP surface energy and the NP distribution pattern in the liver, thereby helping to establish strategies for cell targeting using various NPs.

Advanced Drug Delivery Reviews

“…These cells are known to store vitamin A intracellularly in order to maintain homeostasis [ 46 ]. Comparing the type I collagen a-1 knockdown effect of 3 kinds of ssPalm-LNPs, ssPalmA-LNP showed the highest inhibitory effect on hepatic fibrosis, with an ED 50 of 0.25 mg/kg [ 47 ].…”

Section: Lipid-based Nanoparticles For Sirna Deliverymentioning

confidence: 99%

Recent advances in siRNA delivery mediated by lipid-based nanoparticles

Yonezawa

Koide

Asai

2020

258

157

Small interfering RNA (siRNA) has been expected to be a unique pharmaceutic for the treatment of broad-spectrum intractable diseases. However, its unfavorable properties such as easy degradation in the blood and negative-charge density are still a formidable barrier for clinical use. For disruption of this barrier, siRNA delivery technology has been significantly advanced in the past two decades. The approval of Patisiran (ONPATTRO™) for the treatment of transthyretin-mediated amyloidosis, the first approved siRNA drug, is a most important milestone. Since lipid-based nanoparticles (LNPs) are used in Patisiran, LNP-based siRNA delivery is now of significant interest for the development of the next siRNA formulation. In this review, we describe the design of LNPs for the improvement of siRNA properties, bioavailability, and pharmacokinetics. Recently, a number of siRNA-encapsulated LNPs were reported for the treatment of intractable diseases such as cancer, viral infection, inflammatory neurological disorder, and genetic diseases. We believe that these contributions address and will promote the development of an effective LNP-based siRNA delivery system and siRNA formulation.