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Glycyrrhizin Acid and Glycyrrhetinic Acid Modified Polyethyleneimine for Targeted DNA Delivery to Hepatocellular Carcinoma

1
Center for Bio-nanoengineering and Key Laboratory of Biomass Chemical Engineering, Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
2
Scientific Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou 450058, China
3
Henan province food and drug Administration, Food and Drug Evaluation and Inspection Center, Zhengzhou 450018, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(20), 5074; https://doi.org/10.3390/ijms20205074
Received: 18 September 2019 / Revised: 9 October 2019 / Accepted: 10 October 2019 / Published: 12 October 2019
(This article belongs to the Special Issue Nanomedicine, Nanopharmacy and Nanobiomaterials)
In the last 2–3 decades, gene therapy represented a promising option for hepatocellular carcinoma (HCC) treatment. However, the design of safe and efficient gene delivery systems is still one of the major challenges that require solutions. In this study, we demonstrate a versatile method for covalent conjugation of glycyrrhizin acid (GL) or glycyrrhetinic acid (GA) to increase the transfection efficiency of Polyethyleneimine (PEI, Mw 1.8K) and improve their targeting abilities of hepatoma carcinoma cells. GA and GL targeting ligands were grafted to PEI via N-acylation, and we systematically investigated their biophysical properties, cytotoxicity, liver targeting and transfection efficiency, and endocytosis pathway trafficking. PEI-GA0.75, PEI-GL10.62 and PEI-GL20.65 conjugates caused significant increases in gene transfection efficiency and superior selectivity for HepG2 cells, with all three conjugates showing specific recognition of HepG2 cells by the free GA competition assay. The endocytosis inhibition and intracellular trafficking results indicated that PEI-GA0.75 and GL10.62 conjugates behaved similarly to SV40 virus, by proceeding via the caveolae- and clathrin-independent mediated endocytosis pathway and bypassing entry into lysosomes, with an energy independent manner, achieving their high transfection efficiencies. In the HepG2 intraperitoneal tumor model, PEI-GA0.75 and PEI-GL10.62 carrying the luciferase reporter gene gained high gene expression, suggesting potential use for in vivo application.
Keywords: gene therapy; glycyrrhizin acid; glycyrrhetinic acid; hepatic tumor targeting; caveolae- and clathrin-independent pathway; HepG2 intraperitoneal tumor model gene therapy; glycyrrhizin acid; glycyrrhetinic acid; hepatic tumor targeting; caveolae- and clathrin-independent pathway; HepG2 intraperitoneal tumor model
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Cao, M.; Gao, Y.; Zhan, M.; Qiu, N.; Piao, Y.; Zhou, Z.; Shen, Y. Glycyrrhizin Acid and Glycyrrhetinic Acid Modified Polyethyleneimine for Targeted DNA Delivery to Hepatocellular Carcinoma. Int. J. Mol. Sci. 2019, 20, 5074.

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