Poly-L-Lysine-Lactobionic Acid-Capped Selenium Nanoparticles for Liver-Targeted Gene Delivery.

Shaigan Naidoo,Moganavelli Singh,Saffiya Habib,Aliscia Daniels

doi:10.3390/ijms23031492

Shaigan Naidoo, Moganavelli Singh + Show 2 more

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https://doi.org/10.3390/ijms23031492

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Abstract

Liver cancer is currently regarded as the second leading cause of cancer-related mortality globally and is the sixth most diagnosed malignancy. Selenium nanoparticles (SeNPs) have attracted favorable attention as nanocarriers for gene therapy, as they possess beneficial antioxidant and anticancer properties. This study aimed to design, functionalize and characterize SeNPs to efficiently bind, protect and deliver pCMV–Luc DNA to hepatocellular carcinoma (HepG2) cells. The SeNPs were synthesized by ascorbic acid reduction and functionalized with poly-L-lysine (PLL) to stabilize and confer positive charges to the nanoparticles. The SeNPs were further decorated with lactobionic acid (LA) to target the asialoglycoprotein receptors abundantly expressed on the surface of the hepatocytes. All SeNPs were spherical, in the nanoscale range (<130 nm) and were capable of successfully binding, compacting and protecting the pDNA against nuclease degradation. The functionalized SeNP nanocomplexes exhibited minimal cytotoxicity (<30%) with enhanced transfection efficiency in the cell lines tested. Furthermore, the targeted SeNP (LA–PLL–SeNP) nanocomplex showed significant (* p < 0.05, ** p < 0.01, **** p < 0.0001) transgene expression in the HepG2 cells compared to the receptor-negative embryonic kidney (HEK293) cells, confirming receptor-mediated endocytosis. Overall, these functionalized SeNPs exhibit favorable features of suitable gene nanocarriers for the treatment of liver cancer.

Highlights

Liver cancer has the second-highest cancer-related mortality rate worldwide
The Selenium nanoparticles (SeNPs) were modified and stabilized with the cationic polymer, poly-L-lysine (PLL), which conferred positive charges, and the ligand lactobionic acid (LA), which facilitated targeting of the asialoorosomucoid receptor (ASGP-R), over-expressed on hepatocytes (HepG2 cells)
Tris aminomethane, sodium dihydrogen phosphate, ethylenediamine tetraacetic acid (EDTA), dimethyl sulfoxide (DMSO), 2-(4-(2-hydroxyethyl)-1-piperazinyl) ethane sulphonic acid (HEPES), 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), potassium chloride (KCl), PBS tablets and ethidium bromide were purchased from Merck (Darmstadt, Germany)

Summary

Introduction

Liver cancer has the second-highest cancer-related mortality rate worldwide. It comprises heterogeneous groups of malignant tumors, which include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), mixed hepatocellular cholangiocarcinoma (HCC-CCA), fibrolamellar HCC (FLC) and paediatric neoplasm hepatoblastoma [1,2]. Several pathways may be affected by HCC, including oxidative stress and detoxifying pathways, metabolism of iron pathways and DNA repair mechanisms [5,6]. Current cancer treatments include surgery, radiation therapy and chemotherapy. These treatments have had minimal influence on reducing cancer mortality and become less effective if the tumor cells metastasize to other parts of the body [7]. There are multiple obstacles associated with cancer treatments, including tumour heterogeneity, drug resistance and systematic toxicities throughout the body [8,9]

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