Design and Optimization of Orally Administered Luteolin Nanoethosomes to Enhance Its Anti-Tumor Activity against Hepatocellular Carcinoma.

Mahmoud Elsayed,Tarek Okda,Abd Ramadan,Atef Abd Elbaky,Gamal Atwa,Gamal Omran

doi:10.3390/pharmaceutics13050648

Mahmoud Elsayed, Tarek Okda + Show 4 more

Open Access

https://doi.org/10.3390/pharmaceutics13050648

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Abstract

Luteolin (LUT) is a natural flavonoid with low oral bioavailability with restricted clinical applications due to its low solubility. LUT shows significant anti-tumor activity in many cancer cells, including hepatocellular carcinoma (HCC). The most recent trend in pharmaceutical innovations is the application of phospholipid vesicles to improve the solubility of such hydrophobic drugs. Ethosomes are one of the most powerful phospholipid vesicles used to achieve that that target. In this study, LUT-loaded ethosomal nanoparticles (LUT-ENPs) were prepared by the cold method. Full factorial design and response surface methodology were used to analyze and optimize the selected formulation variables. Drug entrapment efficiency, vesicle size, zeta potential, Fourier transform infra-red spectroscopy, scanning electron microscopy, and cumulative percent drug released was estimated. The selected LUT-ENPs were subjected to further investigations as estimation of hepatic gene expression levels of GPC3, liver biomarkers, and oxidative stress biomarkers. The prepared LUT-ENPs were semi-spherical in shape with high entrapment efficiency. The prepared LUT-ENPs have a small particle size with high zeta potential values. The in vitro liver biomarkers assay revealed a significant decrease in the hepatic tissue nitric oxide (NO), malondialdehyde (MDA) content, and the expression of the GPC3 gene. Results showed a high increase in the hepatic tissue levels of glutathione (GSH) and superoxide dismutase (SOD). Histopathological examination showed a small number of hepatic adenomas and a significant decrease of neoplastic hepatic lesions after treatment with LUT-ENPs. Our results firmly suggest the distinctive anti-proliferative activity of LUT-ENPs as an oral drug delivery system for the treatment of HCC.

Highlights

Hepatocellular carcinoma (HCC) and cholangiocarcinoma are two forms of primary liver cancer that start in the liver tissue
As cancer spreads from other parts of the body to the liver, it is known as secondary metastatic liver cancer [2,3]
The most prevalent type of liver cancer is HCC, which accounts for nearly 90% of all liver cancer [2,4,5]

Summary

Introduction

Based on the previous literature, liver cancer remains the leading cause of cancerrelated deaths worldwide despite, advances in avoidance strategies, yearly checking, and advanced innovations in diagnosis and anticipation [1]. There are two stages of liver cancer, primary and secondary. Hepatocellular carcinoma (HCC) and cholangiocarcinoma are two forms of primary liver cancer that start in the liver tissue (cancer of the bile ducts). As cancer spreads from other parts of the body to the liver, it is known as secondary metastatic liver cancer [2,3]. The most prevalent type of liver cancer is HCC, which accounts for nearly 90% of all liver cancer [2,4,5].

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